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Current Medical Research and Opinion

ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20

An open-label multicenter study to assess the safety of dextromethorphan/quinidine in patients with pseudobulbar affect associated with a range of underlying neurological conditions

Gary L. Pattee, James P. Wymer, Catherine Lomen-Hoerth, Stanley H. Appel, Andrea E. Formella & Laura E. Pope

To cite this article: Gary L. Pattee, James P. Wymer, Catherine Lomen-Hoerth, Stanley H. Appel, Andrea E. Formella & Laura E. Pope (2014) An open-label multicenter study to assess the safety of dextromethorphan/quinidine in patients with pseudobulbar affect associated with a range of underlying neurological conditions, Current Medical Research and Opinion, 30:11, 2255-2265, DOI: 10.1185/03007995.2014.940040 To link to this article: https://doi.org/10.1185/03007995.2014.940040

Accepted author version posted online: 25 Submit your article to this journal Jul 2014. Published online: 28 Jul 2014.

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Download by: ["University at Buffalo Libraries"] Date: 28 November 2017, At: 19:52 Current Medical Research & Opinion Vol. 30, No. 11, 2014, 2255–2265

Original article An open-label multicenter study to assess the safety of dextromethorphan/quinidine in patients with pseudobulbar affect associated with a range of underlying neurological conditions

Gary L. Pattee Abstract Neurology Associates, Lincoln, NE, USA Background: James P. Wymer Pseudobulbar affect (PBA) is associated with neurological disorders or injury affecting the brain, and The Neurosciences Institute, Albany Medical Center, characterized by frequent, uncontrollable episodes of crying and/or laughing that are exaggerated or Albany, NY, USA unrelated to the patient’s emotional state. Clinical trials establishing dextromethorphan and quinidine Catherine Lomen-Hoerth (DM/Q) as PBA treatment were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple Department of Neurology, University of California, San sclerosis (MS). This trial evaluated DM/Q safety in patients with PBA secondary to any neurological condition Francisco, CA, USA affecting the brain. Stanley H. Appel Department of Neurology, Methodist Neurological Objective: Institute, The Methodist Hospital Research Institute, To evaluate the safety and tolerability of DM/Q during long-term administration to patients with PBA The Methodist Hospital, Houston, TX, USA associated with multiple neurological conditions. Andrea E. Formella Methods: Laura E. Pope Fifty-two-week open-label study of DM/Q 30/30 mg twice daily. Safety measures included adverse events Avanir Pharmaceuticals Inc., Aliso Viejo, CA, USA (AEs), laboratory tests, electrocardiograms (ECGs), vital signs, and physical examinations.

Address for correspondence: Clinical trial registration: Gary L. Pattee MD, Neurology Associates, PC, 2631 #NCT00056524. South 70th Street, Lincoln, NE 68506, USA. Tel.: +1 402 483 7226; Fax: +1 402 483 5440; [email protected] Results: Downloaded by ["University at Buffalo Libraries"] 19:52 28 November 2017 A total of 553 PBA patients with430 different neurological conditions enrolled; 296 (53.5%) completed. The most frequently reported treatment-related AEs (TRAEs) were nausea (11.8%), dizziness (10.5%), headache Keywords: (9.9%), somnolence (7.2%), fatigue (7.1%), diarrhea (6.5%), and dry mouth (5.1%). TRAEs were mostly Dextromethorphan/quinidine – Pseudobulbar affect – Safety – Tolerability mild/moderate, generally transient, and consistent with previous controlled trials. Serious AEs (SAEs) were reported in 126 patients (22.8%), including 47 deaths, mostly due to ALS progression and respiratory Accepted: 26 June 2014; published online: 28 July 2014 failure. No SAEs were deemed related to DM/Q treatment by investigators. ECG results suggested no Citation: Curr Med Res Opin 2014; 30:2255–65 clinically meaningful effect of DM/Q on myocardial repolarization. Differences in AEs across neurological disease groups appeared consistent with the known morbidity of the primary neurological conditions. Study interpretation is limited by the small size of some disease groups, the lack of a specific efficacy measure and the use of a DM/Q dose higher than the eventually approved dose.

Conclusions: DM/Q was generally well tolerated over this 52 week trial in patients with PBA associated with a wide range of neurological conditions.

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Introduction were instructed to take DM/Q 30/30 mg in the evening for 7 days and then twice daily thereafter. Patients kept a Pseudobulbar affect (PBA) is a neurological condition that diary of dosage times and recorded any adverse events exerts a significant health burden on patients and care- (AEs). Clinic visits occurred at screening, baseline 1 givers . PBA is associated with a wide range of neuro- (Day 1), and after 1, 4, 8, and 12 months of treatment or logical disorders and is characterized by frequent, sudden, at patient discontinuation. During months when no clinic uncontrollable episodes of crying and/or laughing that are visit was scheduled, patients were contacted by telephone greatly exaggerated or contrary to the patient’s emotional and asked about medication compliance and AEs. state2. Available prevalence studies suggest PBA is present in at least 5% of Parkinson’s disease (PD), 10% of multiple sclerosis (MS), stroke, traumatic brain injury (TBI), and Study population Alzheimer’s disease (AD), 20% of progressive supranuclear palsy, and up to 50% of amyotrophic lateral sclerosis Eligible patients were 18 to 75 years of age with a clinical (ALS) patients3–11. diagnosis of PBA. For the purposes of this study, PBA was PBA is thought to arise from disruption of corticobulbar defined as ‘a syndrome characterized by outbursts of crying and cerebellar/pontine pathways controlling emotional and/or laughing that occur spontaneously and inappropri- expression12–14. These pathways may be disrupted by mul- ately given the context in which they occur’. No specific tiple neurological conditions, yet the ensuing clinical threshold for severity of PBA symptoms was required for manifestations of PBA are indistinguishable, consistent study entry. Patients were required to have an electrocar- with a common etiology across disorders12–14. The com- diogram (ECG) with no evidence of rate-corrected QT bination of dextromethorphan and quinidine (DM/Q) is interval (QTc) prolongation (450 msec in men; the first pharmacotherapy approved by the US Food and 470 msec in women), heart block (isolated right bundle Drug Administration (FDA) and European Medicines branch block without clinical history of heart disease was Authority (EMA) for treating PBA15,16. allowable), sinus bradycardia (550 bpm), ventricular Dextromethorphan (DM) has many pharmacological tachycardia, multifocal ventricular ectopic beats (any fre- actions, including uncompetitive N-methyl-D-aspartate quency), or unifocal ventricular ectopic beats (45/min). (NMDA) receptor antagonism17, sigma-1 receptor agon- Patients with ALS were required to have a vital capacity ism18, and serotonin reuptake inhibition, among others; 50% at baseline. Patients completing prior controlled the precise mechanism(s) accounting for PBA suppression studies of twice daily DM/Q 30/30 mg to treat PBA in 23 22 is/are unknown19. DM is co-administered with low-dose MS or ALS were also eligible to participate, provided quinidine, a potent CYP2D6 inhibitor that reduces rapid they met all eligibility requirements at the time of enroll- first-pass metabolism of DM. This inhibition increases DM ment in this study. bioavailability and half-life20,21. The efficacy, safety, and Exclusion criteria were myasthenia gravis; a history of tolerability of DM/Q as PBA treatment was established in ventricular tachycardia or torsades de pointes; sensitivity three controlled clinical trials lasting 422 or 1223,24 weeks, to quinidine or opiate drugs; major psychiatric disturbance; using fixed-dose combinations of twice daily DM/Q 30/ a history of substance abuse in the past 2 years; any major 30 mg22,23, 30/10 mg24, or 20/10 mg24 in patients with systemic disease that would interfere with interpretation of ALS22,24 or MS23,24. The present trial was designed to pro- study results (e.g., malignancy, uncontrolled diabetes, vide long-term safety data using the higher DM/Q 30/ dilated cardiac myopathy, ischemic or valvular heart

Downloaded by ["University at Buffalo Libraries"] 19:52 28 November 2017 30 mg dose in patients with PBA, regardless of primary disease); hypotension (systolic blood pressure [BP] neurological condition. 5100 mmHg); a history of postural or any unexplained syncope; renal, hepatic, or pulmonary disease; or clinically significant deviations in standard laboratory tests. Female patients could not be pregnant or breastfeeding; those with Methods child-bearing potential were required to use an established Study design method of birth control. Patients were allowed to continue existing medications, Study 02-AVR-107 (NCT00056524) is a multicenter, 52 except for the following starting from 1 week before DM/Q week, open-label safety trial. The trial began in March initiation: ketoconazole, voriconazole, verapamil, diltia- 2003 at 44 sites internationally (39 in the US, four in zem, nifedipine, sodium bicarbonate, carbonic anhydrase Israel, and one in Serbia and Montenegro). An extension inhibitors, thiazide diuretics (unless urine pH 6.5 and on was added to allow completing patients the option to thiazide for 1 month at enrollment), warfarin, haloperi- remain on treatment past 1 year. The trial was terminated dol, monoamine oxidase inhibitors, and tricyclic anti- by the sponsor in June 2007, following the decision to depressants at doses 475 mg/day (420 mg/day for pursue development of a lower DM/Q dose. Patients desipramine; 415 mg/day for protriptyline). Other than

2256 Safety of dextromethorphan/quinidine in PBA Pattee et al. www.cmrojournal.com ! 2014 Informa UK Ltd Current Medical Research & Opinion Volume 30, Number 11 November 2014

the study drug, medications containing dextromethorphan purposes and of anticipated AEs that recipients might or quinidine were prohibited. experience, and ethics committee approval was obtained for each study site. Before any study procedures, a signed informed consent document was obtained. Safety/tolerability assessments Safety and tolerability measures included: AEs recorded in patient diaries and during clinic visits and telephone con- tacts (serious adverse events [SAEs], including deaths, Results were required to be reported through the 30 days following A total of 553 patients with PBA were enrolled (494 in the final dose); vital signs (all visits); resting 12-lead ECG US, 48 in Israel, and 11 in Serbia and Montenegro). (screening, Day 29, and Final Visit at Week 52 or discon- Eighty-nine of these patients entered directly from a tinuation); clinical laboratory values, including serum 12 week, placebo-controlled DM/Q study to treat PBA chemistry, hematology, and urinalysis (screening, Day in MS, and 56 others (9 with ALS and 47 with MS) had 29, and Final Visit); and physical examination (screening been previously exposed to DM and/or quinidine in clin- and Final Visit). ical studies22,23. Over 30 neurological conditions were represented among the participating cohort. In addition to Pharmacokinetic assessments ALS (n ¼ 176) and MS (n ¼ 223), 154 participants had PBA secondary to diverse neurological conditions A blood sample was obtained on Day 29 within 12 h (Table 1). These conditions were categorized into seven after dosing to determine plasma concentrations of DM, disease groups as follows: ALS/motor neuron diseases quinidine, and the DM metabolite dextrorphan (DX). (MND) (n ¼ 199), MS (n ¼ 223), stroke/cerebrovascular disorders (CBVD) (n ¼ 51), TBI (n ¼ 23), PD/movement Safety-data analyses disorders (n ¼ 23), AD/dementia (n ¼ 17), and ‘other PBA’ (n ¼ 17), as shown in Table 1. The safety population comprised all patients receiving at least one DM/Q dose. The numbers of patients experiencing AEs were summarized by body system, relation- Patient disposition ship to study drug, and severity. SAEs and AEs that resulted in study discontinuation were also summarized Patient disposition is shown in Table 2 and duration of descriptively. Additionally, patient demographics, dis- study participation is shown in Figure 1. Of the 553 position, concomitant medications, and AEs were ana- patients treated with DM/Q, 382 patients (69.1%) com- lyzed by primary neurological condition. Likelihood-ratio pleted at least 6 months of treatment, 300 (54.2%) com- chi-square tests were used to compare AE incidence pleted 1 year, and 296 (53.5%) completed the protocol- among disease groups. Assignment of patients to sub- specified visits. One hundred forty-eight (26.8%) patients groups for analysis by primary neurological condition dropped out of the trial for either an AE or medication was made based on similarities among nosological refusal due to an AE; 109 (19.7%) dropped out for other characteristics and without knowledge of patient data reasons. Of the completers, 262 (88.5%) elected to con- or safety outcome. tinue DM/Q in the optional extension. At trial termin- Clinical laboratory values were summarized descrip- Downloaded by ["University at Buffalo Libraries"] 19:52 28 November 2017 ation, 20 patients (3.6%) remained in the treatment phase tively; shifts between normal, low, or high values were and 168 (64.1% of those entering the extension) remained analyzed using McNemar’s test. Changes in physical- in the extension. This report provides results from the 52 examination findings (normal vs. abnormal) were assessed week treatment phase. by McNemar’s test. Summary statistics of absolute values and percentage change from screening value were provided for systolic and diastolic BP, heart rate, respiratory rate, QT interval, QTc interval, ventricular rate, PR inter- Patient demographics val, and QRS duration. Clinically significant abnormal- Patient demographics by primary disease are provided in ities were documented. Table 3. Patients reported a median of 7.0 (range 0–420; mean 16.7 32.6) PBA episodes per week at baseline. Ethics and Good Clinical Practice Some patients transitioned directly from a previous DM/ Q study and therefore may have had low or no PBA epi- The study was conducted in conformity with the standards sodes at baseline. The median patient age was 52.0 years of Good Clinical Practices and the Declaration of (range 18–86), 15.9% were 65 years old, 58.2% were Helsinki. Eligible patients were informed of the study’s female, and 90.8% were Caucasian.

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Concurrent medications Patients were taking a median of seven additional medications at baseline (range 0–30) including those for 17) their primary neurological condition and other conditions. ¼ n (

Other PBA The number of baseline medications was similar for study completers and those who discontinued for AEs. The most frequently reported concurrent chronic

HydrocephalusPost-encephalitisFoster-Kennedy syndromeNone known 1 1 1 medications 1 (taken 3 months during treatment) were nonsteroidal anti-inflammatory drugs and other anal- 5 Small-fiber neuropathy 1 gesics, antidepressants, lipid-modifying agents, antithrombotics, inhibitors of gastric acid production, vitamins, anticonvulsants, and benzodiazepines (Table 4). Antipsychotics were used chronically by 2.2% of patients. 23)

¼ Common disease-specific therapies included: interferon n ( disorders

PD/movement beta, glatiramer, baclofen, and stimulants in patients with MS; donepezil, and memantine in patients with on disease; MS: multiple sclerosis; PBA: pseudobulbar affect; PD:

palsy AD; riluzole in patients with ALS; dopaminergic drugs

Choreiform disorderMovement disorderCorticobasilar degeneration 1 1 Viral 1 meningio-encephalitis Post-herpes simplex virus Subdural 1 hematoma 1 in 1 patients with PD; antithrombotics and cardiovascular medications in patients with stroke; and antiepileptics 2 Parkinson syndrome 1 Spinocerebellar ataxia 2 in patients with TBI (Table 5). 23) TBI ¼ n ( trauma Adverse events Over 90% of patients (n ¼ 508; 91.8%) reported at least 1 Parkinsonian syndrome 1 Chronic cough 1 5 Atypical PD 1 Cerebral palsy 2

16 Head one AE during the 52 week trial. The most frequently reported AEs (incidence 15%) were nausea, headache, dizziness, fall, and diarrhea. Most AEs were mild to moderate in severity (64.8% of patients with AEs). Table 6 199) shows the incidence of commonly reported AEs across ¼ n ( ALS/MND

). disease groups. n Although chi-square tests were performed for each AE, resulting p values must be regarded as exploratory due to sclerosis disease or degeneration palsy multiple comparisons and the small size of some groups. Differences in AE incidence across disease groups appeared 1 Bulbar motor neuron consistent with the expected manifestations of the primary neurological conditions. For example, respiratory failure occurred exclusively, and dysphagia and dyspnea predominantly, in ALS/MND patients; fatigue was more than 51) ¼ Downloaded by ["University at Buffalo Libraries"] 19:52 28 November 2017 twice as common in TBI patients; somnolence was most n (

Stroke/CBVD common in PD/movement disorders patients; weakness was most common in ALS/MND and MS patients; and

surgery constipation was most common in AD/dementia, ALS/ Brain aneurysm 1 Bulbar palsy 1 Progressive supranuclear Pontine AVMPost-cerebral aneurysm Subarachnoid hemorrhage 1 1 Progressive bulbar MND, and ‘other PBA’ patients. Huntington’s disease 1 Leuko-encephalopathy 1 Because of the high morbidity associated with several neurological conditions, it seems particularly important to 223) MS ¼ also note the frequency of AEs that investigators con- n ( sidered possibly related to DM/Q treatment (TRAEs) (Table 7). Most TRAEs (91%) were mild-to-moderate 2 Venous angioma 1 Primary lateral in severity. Only seven occurred with incidence 5%: nausea (11.8%), dizziness (10.5%), headache (9.9%), somnolence (7.2%), fatigue (7.1%), diarrhea (6.5%), and Categorization of patients’ primary neurological conditions into disease groups (

dementia dry mouth (5.1%). 17)

¼ To further assess the time course of these seven TRAEs, n AD/dementia ( ADFrontal lobe 15 MS 223 Stroke 46 ALS 176 TBI 21 PD 11 Cerebellar ataxia 3 AD: Alzheimer’s disease; ALS:Parkinson’s disease; amyotrophic TBI: lateral traumatic sclerosis; brain injury. AVM: arteriovenous malformation; CBVD: cerebrovascular disorders; MND: motor neur

Table 1. a post hoc analysis was conducted evaluating time to onset,

2258 Safety of dextromethorphan/quinidine in PBA Pattee et al. www.cmrojournal.com ! 2014 Informa UK Ltd Current Medical Research & Opinion Volume 30, Number 11 November 2014

Table 2. Patient disposition by primary neurological conditiona.

Patient disposition, n AD/dementia MS Stroke/CBVD TBI ALS/MND PD/movement Other Total disorders PBA

Enrolled n ¼ 17 n ¼ 223 n ¼ 51 n ¼ 23 n ¼ 199 n ¼ 23 n ¼ 17 N ¼ 553 Treated 6 months 10 176 30 15 126 12 13 382 Treated 12 monthsa 5 149 27 10 86 11 12 300 Completed treatment phase 4 149 27 9 85 10 12 296 Remaining at study termination 2 8 4 2 4 0 0 20 Did not complete due to: 11 66 20 12 110 13 5 257 AE 4 27 7 1 62 5 1 107 Medication refusal due to AE 2 10 4 2 18 4 1 41 Medication refusal for other than AE 0 7 1 2 3 0 1 14 Withdrew consent 3 15 3 3 9 1 0 34 Lost to follow-up 0 4 4 2 7 0 1 18 Protocol violation 0 2 0 0 1 0 0 3 Other 4 9 5 4 14 3 1 40 Entered extension phase 4 132 22 8 77 8 11 262

AD: Alzheimer’s disease; AE: adverse event; ALS: amyotrophic lateral sclerosis; CBVD: cerebrovascular disorders; MND: motor neuron disease; MS: multiple sclerosis; PBA: pseudobulbar affect; PD: Parkinson’s disease; TBI: traumatic brain injury. aIncludes all patients who completed the treatment phase or received at least 365 days of dosing.

100 median duration but did decrease estimates of AE persist- 90 ence (Online Resource 1).

70 Serious adverse events 60 The overall incidence of SAEs was 22.8%; no SAE was 50 reported to be related to study medication. Most SAEs occurred in patients with ALS/MND, including all SAEs 40 of respiratory failure, dysphagia, and pneumonia (Online 30 Resource 2). Except for respiratory events in ALS and disease exacerbation in MS, there was no evidence of

Patients Remaining in Study (%) 20 increased frequency of SAEs specific to any neurological 10 disorder. 0 Forty-seven deaths occurred during the 52 week trial, 0 4 8 1216202428323640444852 most attributed to ALS progression. Thirty-one of the 39 Study Week ALS deaths were attributed to ALS-related respiratory Figure 1. Proportion of patients remaining in study, by study week. failure or similar respiratory events. The remaining eight were attributed to ‘ALS progression’ (n ¼ 3), cardiac arrest (n ¼ 2), pneumonia (n ¼ 1), infection (n ¼ 1), and cardio-

Downloaded by ["University at Buffalo Libraries"] 19:52 28 November 2017 respiratory arrest and epistaxis (n ¼ 1). One additional duration, recurrence, and percentage of total study days ALS/MND group patient with primary lateral sclerosis with TRAE present (persistence) (Online Resource 1). died of ‘cause unknown’. Following study completion, an Common TRAEs generally occurred early in therapy and investigator query about all ALS patient deaths provided were transient; both median time to onset and duration an estimated median time from ALS diagnosis to death of ranged from 4 to 8 days for all but fatigue (median duration 29 months. (Actual date of death was obtained for 117 16 days). TRAEs did not recur in most patients; the high- patients; the remainder were censored at date of last con- est incidence of recurrence was headache (42% recurrence tact.) The three deaths in MS patients were attributed to after initial episode). TRAE presence as a percentage of acute myelomonocytic leukemia, myocardial infarction total treatment days was low, ranging from a median of 2% (patient with resolving flu-like illness and extensive pre- for dizziness and headache to 22% for fatigue and sleepi- existing skin breakdown; received DM/Q for 8 days and ness. Inclusion of patients who discontinued prior to AE then discontinued for recurrent flu-like illness, hallucin- resolution can reduce estimates of AE duration while ations, and lethargy; and died 5 days later), and myocardial increasing estimates of percentage of treatment days with infarction and sepsis (patient with pulmonary embolism AE present (by decreasing total treatment days). Omitting and sepsis). Of the remaining four deaths, two were attrib- these patients from this analysis did not appreciably affect uted to stroke (patient with AD and prior stroke history

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Table 3. Patient demographics by primary neurological condition.

Category AD/dementia MS Stroke/CBVD TBI ALS/MND PD/movement Other PBA (n ¼ 17) (n ¼ 223) (n ¼ 51) (n ¼ 23) (n ¼ 199) disorders (n ¼ 17) (n ¼ 23)

Age (years) Mean 63.5 45.7 54.8 45.6 55.6 64.9 49.1 SD 11.20 10.23 10.93 13.81 11.06 8.00 13.71 Median 66.0 47.0 56.0 44.0 57.0 66.0 52.0 Min, max 38, 79 18, 71 30, 80 18, 74 18, 80 50, 86 22, 67 Gender, n (%) Male 10 (58.8) 49 (22.0) 24 (47.1) 10 (43.5) 116 (58.3) 15 (65.2) 7 (41.2) Female 7 (41.2) 174 (78.0) 27 (52.9) 13 (56.5) 83 (41.7) 8 (34.8) 10 (58.8) Ethnicity, n (%) Caucasian 16 (94.1) 208 (93.3) 43 (84.3) 18 (78.3) 179 (89.9) 22 (95.7) 16 (94.1) Black 1 (5.9) 5 (2.2) 5 (9.8) 1 (4.3) 5 (2.5) 0 (0) 0 (0) Asian 0 (0) 1 (0.4) 1 (2.0) 0 (0) 1 (0.5) 0 (0) 0 (0) Hispanic 0 (0) 8 (3.6) 2 (3.9) 3 (13.0) 9 (4.5) 1 (4.3) 1 (5.9) Other 0 (0) 1 (0.4) 0 (0) 1 (4.3) 5 (2.5) 0 (0) 0 (0)

AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; CBVD: cerebrovascular disorders; MND: motor neuron disease; MS: multiple sclerosis; PBA: pseudobulbar affect; PD: Parkinson’s disease; SD: standard deviation; TBI: traumatic brain injury.

Table 4. Common concurrent medicationsa by primary neurological condition.

Description, % AD/dementia MS Stroke/CBVD TBI ALS/MND PD/movement Other PBA Total (n ¼ 17) (n ¼ 223) (n ¼ 51) (n ¼ 23) (n ¼ 199) disorders (n ¼ 17) (N ¼ 553) (n ¼ 23)

NSAIDs 23.5 36.3 19.6 30.4 40.2 17.4 5.9 33.8 Antidepressants 23.5 23.3 31.4 30.4 29.1 34.8 23.5 26.9 Tricyclic antidepressants 0 4.9 2.0 13.0 13.1 4.3 0 7.6 SSRIs 5.9 15.2 21.6 17.4 10.6 13.0 5.9 13.6 Otherb 17.6 8.1 7.8 8.7 10.1 17.4 17.6 9.8 Lipid modifiers 35.3 22.4 35.3 21.7 20.6 13.0 23.5 23.0 Antithrombotics 35.3 12.1 52.9 17.4 24.6 21.7 5.9 21.5 Analgesics (e.g., acetaminophen) 35.3 25.6 19.6 21.7 14.1 13.0 5.9 19.9 Drugs to inhibit gastric acid 23.5 15.7 23.5 21.7 22.6 17.4 23.5 19.7 production Vitamin E 11.8 7.6 3.9 4.3 37.7 8.7 29.4 18.8 Antiepileptics 17.6 23.8 25.5 43.5 9.0 8.7 29.4 18.8 Multivitamins, plain 5.9 22.4 7.8 8.7 20.1 0 11.8 17.9 Anxiolytics 23.5 16.6 11.8 13.0 20.1 21.7 11.8 17.5 Vitamin C 11.8 12.6 0 4.3 30.7 8.7 0 17.0 Antihistamines for systemic use 17.6 14.8 7.8 26.1 18.1 4.3 17.6 15.6 Vitamin B12 and folic acid 11.8 9.9 7.8 17.4 20.1 4.3 11.8 13.6 Calcium 5.9 20.2 7.8 8.7 7.5 17.4 5.9 13.0 Hypnotics and sedatives 17.6 8.5 3.9 4.3 20.6 17.4 0 12.7 Opioids 11.8 11.7 5.9 8.7 15.1 4.3 11.8 11.9 Laxatives 11.8 9.4 5.9 4.3 17.1 0 11.8 11.4 Downloaded by ["University at Buffalo Libraries"] 19:52 28 November 2017 Misc. herbal 0 13.0 2.0 0 15.1 0 0 10.8 Beta-blocking agents 11.8 6.7 13.7 4.3 13.1 17.4 5.9 10.1 Thyroid preparations 17.6 9.4 9.8 17.4 7.5 13.0 5.9 9.4 ACE inhibitors, plain 17.6 5.8 19.6 13.0 9.0 4.3 11.8 9.0

ACE: angiotensin-converting enzyme; AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; CBVD: cerebrovascular disorders; MND: motor neuron disease; MS: multiple sclerosis; NSAIDs: nonsteroidal anti-inflammatory drugs; PBA: pseudobulbar affect; PD: Parkinson’s disease; SSRI: selective serotonin reuptake inhibitor; TBI: traumatic brain injury. aUsed for 3 months and taken during the study; drug use represents minimum use in each category and may not include some combination products such as antihistamine cold products, combinations of vitamins and herbals, etc. bOther includes: venlafaxine, 3.6%; bupropion, 3.3%; trazodone, 2.5%; mirtazepine, 1.3%; duloxetine, mianserin, nefazodone, reboxetine, and hydroxytryptophan, 0.2% (1 patient) each.

who died on Day 217, and a patient with prior stroke and reactive depression). In all cases, death was considered history who died on Day 41); one was attributed to cardiac unlikely related to DM/Q treatment. All deaths occurring arrest (patient with AD and history of acute coronary during the complete DM/Q clinical development program syndrome and hypertension); and one patient committed were additionally reviewed by a group of consulting cardi- suicide on Day 104 (patient with spinocerebellar ataxia ologists and neurologists as part of the FDA review process

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Table 5. Common concurrent disease-specific medicationsa by primary for the DM/Q application for treatment of PBA. Their neurological condition. findings corroborated the investigators’ initial assessment that the deaths were not related to treatment but to pro- AD/dementia (n ¼ 17) % Anticholinesterase (e.g., donepezil) 47.1 gression of underlying neurological or other medical Memantine 29.4 conditions. MS (n ¼ 223) % Interferon beta 45.3 Glatiramer 27.4 AEs leading to discontinuation Centrally acting muscle relaxants (e.g., baclofen, 33.2 tizanidine, orphenadrine) One hundred forty-nine patients (26.9%) withdrew from Urinary antispasmodics (e.g., oxybutynin, tolterodine) 25.6 the trial or refused further study medication due to AEs Psychostimulants (e.g., amphetamine derivatives, 18.8 modafinil, pemoline) (Online Resource 3). This number includes one discon- Glucocorticoids 5.8 tinuation during the extension for an AE beginning in the Immunosuppressants (e.g., methotrexate, 5.8 treatment phase. AE dropout was more frequent in ALS/ mycophenolate, azathioprine) Mitoxantrone 4.0 MND (n ¼ 80; 40.2% of ALS/MND patients), PD/move- 4-Aminopyridine 2.2 ment disorders (n ¼ 9; 39.1% of PD/movement disorders Stroke/CBVD (n ¼ 51) % patients), and AD/dementia (n ¼ 6; 35.3% of AD/demen- Aspirin 43.1 tia patients), and less frequent in stroke/CBVD (n ¼ 11; Clopidogrel 19.6 21.5%), MS (n ¼ 37; 16.6%), TBI (n ¼ 3; 13.0%), and Calcium channel blockers (e.g., dihydropyridine) 11.8 ‘other PBA’ (n ¼ 2; 11.8%). The most common AEs lead- TBI (n ¼ 23) % ing to discontinuation were respiratory failure in ALS/ Topiramate 13.0 Carbamazepine/oxcarbazepine 13.0 MND patients (14.1% of ALS/MND group; 5.1% of Thyroid preparations 17.4 total), nausea (3.3%), dizziness (2.9%), headache Psychostimulants (e.g., amphetamine derivatives, 13.0 (2.5%), and diarrhea (1.8%). Other than respiratory modafinil, pemoline) Antimigraine (e.g., triptans, selective 5HT1 agonists) 13.0 failure and nausea in the ALS/MND group and dizziness Glucocorticoids 8.7 and headache in the PD/movement disorders group, ALS/MND (n ¼ 199) % discontinuation due to AEs appeared similar regardless Riluzole 47.7 of primary neurological disorder. Approximately half of Centrally acting muscle relaxants (e.g., baclofen, 31.7 the AE-related dropouts, (n ¼ 74 or 13.5% of total tizanidine, orphenadrine) Coenzyme Q10 31.2 patients) included AEs that were judged to be at least Tetracycline antibiotics (e.g., minocycline, doxycycline) 17.6 possibly related to treatment. In these patients, the Creatine 15.6 median time to discontinuation was 16.5 days (mean Beta-2-adrenergic agonists, inhalants 14.6 Beta carotene/vitamin A 13.1 31.4; range 1–243). Urinary antispasmodics (e.g., oxybutynin, tolterodine) 11.1 Quinine 10.6 Expectorants and mucolytics (e.g., guaifenesin, 9.0 Clinical laboratory values and vital signs n-acetylcysteine) Belladonna alkaloids (e.g., atropine, hyocyamine, 9.0 Laboratory test results remained stable during the trial. scopolamine) Glycopyrrolate 7.5 Shift tables showed no changes of clinical relevance. There were no clinically relevant changes in mean systolic PD/movement disorders (n ¼ 23) % Dopamine derivatives ( carbidopa, benserazide, 65.2 and diastolic BP, heart rate, respiratory rate, or body tem- Downloaded by ["University at Buffalo Libraries"] 19:52 28 November 2017 or entacapone) perature at any visit. Increased BP was recorded as an AE Dopamine agonists 30.4 in 11 patients (2.0%), and increased systolic BP was Amantadine 17.4 Selegiline 8.7 recorded as an AE in one patient; however, these were Trihexyphenidyl 0.5 considered ‘not related’ or ‘unlikely related’ to DM/Q Other PBA (n ¼ 17) % treatment in all but one patient (‘possibly related’). Phenytoin 11.8 Tiagabine 11.8 Physical examinations 5HT1: type 1 5-hydroxytryptamine (serotonin) receptor; AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; CBVD: cerebrovascular dis- No abnormal physical findings related to study-drug treat- orders; MND: motor neuron disease; MS: multiple sclerosis; PBA: pseudobulbar affect; PD: Parkinson’s disease; TBI: traumatic brain injury. ment were observed. aUsed for 3 months and taken during the study. Electrocardiography Mean ECG values showed no clinically relevant post-baseline changes (Online Resource 4). QTc intervals showed a

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Table 6. Incidence of adverse events reported by 5% and at least two patients in any primary-neurological-condition category (safety population).

Preferred AD/dementia MS Stroke/ TBI ALS/MND PD/movement Other PBA p Valuea Total term, % (n) (n ¼ 17) (n ¼ 223) CBVD (n ¼ 23) (n ¼ 199) disorders (n ¼ 17) (N ¼ 553) (n ¼ 51) (n ¼ 23)

Any AE 70.6 (12) 89.7 (200) 90.2 (46) 82.6 (19) 98.0 (195) 91.3 (21) 88.2 (15) 0.0004 91.9 (508) Nausea 11.8 (2) 23.8 (53) 19.6 (10) 13.0 (3) 31.7 (63) 8.7 (2) 23.5 (4) 0.0544 24.8 (137) Headache 5.9 (1) 25.1 (56) 15.7 (8) 26.1 (6) 22.1 (44) 26.1 (6) 29.4 (5) 0.4613 22.8 (126) Dizziness 5.9 (1) 21.5 (48) 19.6 (10) 21.7 (5) 17.1 (34) 30.4 (7) 17.6 (3) 0.5201 19.5 (108) Fall 17.6 (3) 13.5 (30) 7.8 (4) 13.0 (3) 22.6 (45) 21.7 (5) 5.9 (1) 0.0674 16.5 (91) Diarrhea 23.5 (4) 15.7 (35) 11.8 (6) 13.0 (3) 19.1 (38) 0 (0) 23.5 (4) 0.2426 16.3 (90) Fatigue 17.6 (3) 16.6 (37) 7.8 (4) 39.1 (9) 11.1 (22) 13.0 (3) 17.6 (3) 0.0141 14.6 (81) Weakness 0 (0) 14.8 (33) 3.9 (2) 4.3 (1) 18.6 (37) 4.3 (1) 11.8 (2) 0.0245 13.7 (76) Nasopharyngitis 0 (0) 16.1 (36) 9.8 (5) 13.0 (3) 9.5 (19) 4.3 (1) 11.8 (2) 0.1944 11.9 (66) Somnolence 5.9 (1) 4.9 (11) 15.7 (8) 4.3 (1) 15.6 (31) 26.1 (6) 11.8 (2) 0.0019 10.8 (60) Arthralgia 0 (0) 14.3 (32) 5.9 (3) 0 (0) 10.1 (20) 13.0 (3) 5.9 (1) 0.1334 10.7 (59) Cough 5.9 (1) 10.3 (23) 3.9 (2) 13.0 (3) 14.6 (29) 4.3 (1) 0 (0) 0.1633 10.7 (59) Ecchymosis 5.9 (1) 8.1 (18) 5.9 (3) 4.3 (1) 12.6 (25) 13.0 (3) 17.6 (3) 0.4343 9.8 (54) Pain in limb 0 (0) 13.0 (29) 11.8 (6) 0 (0) 8.5 (17) 0 (0) 5.9 (1) 0.1056 9.6 (53) Constipation 11.8 (2) 5.4 (12) 5.9 (3) 0 (0) 15.1 (30) 4.3 (1) 11.8 (2) 0.0124 9.0 (50) Insomnia 0 (0) 6.7 (15) 7.8 (4) 8.7 (2) 13.6 (27) 0 (0) 11.8 (2) 0.1004 9.0 (50) Back pain 5.9 (1) 9.9 (22) 5.9 (3) 0 (0) 9.0 (18) 4.3 (1) 5.9 (1) 0.6684 8.3 (46) Dysphagia 0 (0) 1.8 (4) 3.9 (2) 0 (0) 20.1 (40) 0 (0) 0 (0) 50.0001 8.3 (46) Dry mouth 5.9 (1) 5.8 (13) 9.8 (5) 0 (0) 8.5 (17) 13.0 (3) 0 (0) 0.4119 7.1 (39) Edema lower limb 5.9 (1) 3.6 (8) 7.8 (4) 8.7 (2) 9.5 (19) 8.7 (2) 11.8 (2) 0.3244 6.9 (38) Respiratory failure 0 (0) 0 (0) 0 (0) 0 (0) 19.1 (38) 0 (0) 0 (0) 50.0001 6.9 (38) Sore throat 5.9 (1) 9.0 (20) 3.9 (2) 4.3 (1) 7.0 (14) 0.4887 6.9 (38) Urinary tract 0 (0) 9.9 (22) 5.9 (3) 4.3 (1) 4.5 (9) 4.3 (1) 11.8 (2) 0.2970 6.9 (38) infection Dyspnea 0 (0) 3.6 (8) 3.9 (2) 8.7 (2) 11.6 (23) 4.3 (1) 5.9 (1) 0.0399 6.7 (37) Fatigue aggravated 0 (0) 9.4 (21) 3.9 (2) 0 (0) 5.0 (10) 0 (0) 5.9 (1) 0.1663 6.1 (34) Laceration 0 (0) 5.8 (13) 5.9 (3) 0 (0) 8.0 (16) 4.3 (1) 5.9 (1) 0.6724 6.1 (34) MS aggravated 0 (0) 14.3 (32) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 50.0001 5.8 (32) Pyrexia 5.9 (1) 7.6 (17) 3.9 (2) 5.0 (10) 4.3 (1) 5.9 (1) 0.7549 5.8 (32) Vomiting 5.9 (1) 7.6 (17) 2.0 (1) 8.7 (2) 5.0 (10) 4.3 (1) 0 (0) 0.6161 5.8 (32) Muscle spasms 0 (0) 6.7 (15) 0 (0) 8.7 (2) 6.0 (12) 0 (0) 5.9 (1) 0.3610 5.4 (30) Nasal congestion 0 (0) 6.3 (14) 3.9 (2) 4.3 (1) 6.0 (12) 0 (0) 0 (0) 0.6634 5.2 (29) Anxiety 0 (0) 3.6 (8) 0 (0) 4.3 (1) 7.5 (15) 13.0 5.9 (1) 0.1138 5.1 (28) Joint stiffness 0 (0) 5.4 (12) 2.0 (1) 0 (0) 6.5 (13) 0 (0) 11.8 (2) 0.3292 5.1 (28)

Table 7. Incidence of treatment-relateda adverse events by primary neurological condition (safety population).

Preferred term, % AD/dementia MS Stroke/CBVD TBI ALS/MND PD/movement Other PBA Total (n ¼ 17) (n ¼ 223) (n ¼ 51) (n ¼ 23) (n ¼ 199) disorders (n ¼ 17) (N ¼ 553)

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Any TRAE 23.5 39.9 51.0 47.8 59.3 60.9 52.9 49.0 Nausea 0 8.1 7.8 4.3 19.1 4.3 17.6 11.8 Dizziness (excluding vertigo) 0 10.3 7.8 13.0 10.1 21.7 17.6 10.5 Headache NOS 0 9.4 5.9 8.7 11.6 21.7 5.9 9.9 Somnolence 0 2.7 5.9 0 13.1 13.0 11.8 7.2 Fatigue 5.9 5.8 2.0 26.1 7.5 4.3 11.8 7.1 Diarrhea NOS 11.8 4.0 3.9 4.3 9.0 0 23.5 6.5 Dry mouth 0 3.1 5.9 0 8.0 8.7 0 5.1

Additional TRAEs that occurred in at least 5% of patients and in two or more patients in any disease category were stroke/CBVD: insomnia (not elsewhere classified), n ¼ 3 (5.9%); TBI: lethargy, n ¼ 3 (13.0%), abnormal dreams, n ¼ 2 (8.7%); ALS/MND: constipation, n ¼ 11 (5.5%); PD/movement disorders: confusion, n ¼ 2 (8.7%); other PBA: joint stiffness, n ¼ 2 (11.8%); flatulence, n ¼ 2 (11.8%); dyspepsia, n ¼ 2 (11.8%). AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; CBVD: cerebrovascular disorders; MND: motor neuron disease; MS: multiple sclerosis; NOS: not otherwise specified; PBA: pseudobulbar affect; PD: Parkinson’s disease; TRAE: treatment-related adverse event. aTRAEs that occurred in at least 5% of total patients; treatment-related categories included possible, probable, highly probable, and missing.

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small mean increase (QTcF 3.2; QTcB 4.6 msec) from disease group, AE data from DM/Q double-blind trials, baseline to final measurement. Five patients had QTc and literature-reported mortality patterns in ALS increases 60 msec; however, all values remained patients22–26. Overall, the 39/176 ALS patient deaths con- 5500 msec during the 52 week treatment phase. stitute a mortality rate of 22.2%, which is lower than the death rate reported in prospective trials. In large-scale ALS-treatment trials, 1 year mortality rates ranged from Pharmacokinetics approximately 26% to 35% in treatment arms and as high 27,28 Blood samples were provided by 202 patients on Day 29. as 46% in placebo arms . Furthermore, epidemiological Mean (standard deviation) plasma concentrations were studies generally suggest median survival after ALS diag- 29–34 DM: 92.7 (45.6) ng/mL, DX: 78.0 (43.4) ng/mL, and quini- nosis is approximately 15 to 19 months , although at dine: 0.15 (0.09) mg/mL. Mean DM concentration was least one study has reported median survival post-diagnosis 35 similar to that reported in previous placebo-controlled of 30 months . The median survival after ALS diagnosis trials using this dosage22,23. in the current study was estimated at 29 months (n ¼ 176); however, inferences regarding potential effect of DM/Q on survival are not possible without controlled studies. Discussion The DM/Q 30/30 mg twice daily dosage administered in this study is greater than the DM/Q 20/10 mg twice daily Long-term administration of DM/Q was well tolerated in dosage approved by the FDA and EMA for PBA treatment this large, open-label study of patients with PBA associated and also greater than the 30/10 mg twice daily dosage with a wide range of neurological conditions. These results approved by the EMA. Given that the incidence of some provide important safety data for DM/Q, the only TRAEs, such as dizziness and nausea, appear dose-related approved medication for PBA, a common and distressing in controlled trials22–24, it is likely that the AE incidence disorder experienced by patients with neurologic disease or reported in this long-term study would be greater than injury. The low incidence of treatment-emergent AEs with observed with the lower approved doses. Indeed, among DM/Q used at a higher dose than the approved dose, and patients treated with DM/Q 20/10 mg for 12 weeks during occurring in a diverse, clinic-based, ‘real-world’ popula- the pivotal trial (n ¼ 107) the percentages reporting head- tion, provides reassuring clarity for physicians on the ache, dizziness, and nausea were 14.0%, 10.3%, and 7.5%24 risks of this treatment. The overall incidence of reported versus 22.8%, 19.5%, and 24.8%, respectively, in the pre- AEs is consistent with the trial length and chronic and sent study. often progressive nature of the underlying neurological Quinidine is a potent and reliable inhibitor of CYP2D6, conditions. Although the majority (90%) of patients and the dose in the approved DM/Q formulation (10 mg reported at least one AE, only 49% reported AEs possibly twice daily) is sufficient to increase DM exposure approxi- related to DM/Q treatment, and only 13.4% discontinued mately 20-fold24. Other medications metabolized by for TRAEs. The most frequently reported AEs were con- CYP2D6 include antidepressants, antipsychotics, and sistent with those reported at higher incidence than con- beta-blockers. While concentrations of these medications trols in shorter, double-blind DM/Q 30/30 mg trials in may be increased in the presence of quinidine, potential PBA patients with ALS or MS22,23. In a 4 week study in drug interactions can be managed with simple dose adjust- ALS patients22, the most commonly reported AEs (inci- ments. The overall number and type of concomitant medi- dence 15% and more than controls) among DM/Q cations taken in this study appear to reflect those seen in

Downloaded by ["University at Buffalo Libraries"] 19:52 28 November 2017 recipients (n ¼ 70) were nausea, dizziness, fatigue, diar- typical clinical practice. Patients who withdrew from the rhea, and headache. In a 12 week study in MS patients23, study for AEs did not appear to have a higher medication the most commonly reported AEs (incidence 15% and burden than those who completed the trial. more than placebo) among the DM/Q recipients (n ¼ 76) While quinidine is a well established type 1a antiar- were dizziness, nausea, and headache. rhythmic drug with potential to cause dose-related This patient population is susceptible to falls. Falls were QT-interval prolongation36, ventricular arrhythmia, and reported by 16.5% of patients in this study; however, only torsades de pointes37–40, no clinically significant arrhyth- six patients (1.1%) experienced a fall that was deemed by mias were reported in controlled trials of DM/Q for PBA investigators as possibly related to treatment. In double- utilizing either the 30 or 10 mg doses of quinidine22–24.No blind clinical trials falls were reported with similar inci- patient had QTc increase4500 msec during the treatment dence in DM/Q and placebo recipients. phase. Two patients (both with MS) had a QTc4500 msec Several types of AEs, particularly SAEs, were during the elective treatment extension; one had QTcB/ attributed to primary neurological conditions, for example QTcF ¼ 493/505 msec and was withdrawn from the trial, respiratory depression, dyspnea, and dysphagia in ALS and the other had prolonged QTc on two occasions (high- and disease aggravation in MS. Underlying disease est QTcB/QTcF ¼ 526/506 msec on Day 1183) and contribution to AEs is supported by the AE analysis by remained in treatment until study termination. Overall

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ECG results suggested no clinically meaningful effect of management; Adrian Hepner MD, previously of Avanir DM/Q on myocardial repolarization or any ECG variable. Pharmaceuticals Inc., for contributing to the analysis of the In summary, no significant ECG changes were observed study and the early stages of this manuscript; Joao Siffert MD on DM/Q during this 1 year study. The observed TRAEs of Avanir Pharmaceuticals Inc. and Randall E. Kaye MD, previ- occurred early in the treatment course, were largely mild- ously of Avanir Pharmaceuticals Inc., for critical review of the to-moderate, predominantly transient, and typically did data and manuscript; and The Curry Rockefeller Group LLC for help in preparing the manuscript for publication. not result in discontinuation. The safety and tolerability profile of DM/Q in this study was consistent with that observed in previous DM/Q trials, and the outcomes for patients receiving DM/Q followed the anticipated clinical course of the underlying neurological conditions. References 1. Colamonico J, Formella A, Bradley W. Pseudobulbar affect: burden of illness in the USA. Adv Ther 2012;29:775-98 2. Wortzel HS, Oster TJ, Anderson CA, Arciniegas DB. Pathological laughing Key points and crying: epidemiology, pathophysiology and treatment. CNS Drugs 2008;22:531-45 3. Parvizi J, Arciniegas DB, Bernardini GL, et al. Diagnosis and management of Pseudobulbar Affect (PBA) is an uncontrollable dis- pathological laughter and crying. Mayo Clin Proc 2006;81:1482-6 order of emotional expression, occurring in a broad 4. Work S, Colamonico JA, Bradley WG, Kaye RE. Pseudobulbar affect: an range of neurological diseases or injuries affecting the under-recognized and undertreated neurological disorder. 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Parvizi J, Joseph J, Press DZ, Schmahmann JD. Pathological laughing and crying in patients with multiple system atrophy-cerebellar type. Mov Disord and received research support from Avanir Pharmaceuticals Inc. 2007;22:798-803 Downloaded by ["University at Buffalo Libraries"] 19:52 28 November 2017 C.L.-H. has disclosed that she has no significant relationships 14. Parvizi J, Coburn KL, Shillcutt SD, et al. Neuroanatomy of pathological with or financial interests in any commercial companies related laughing and crying: a report of the American Neuropsychiatric to this study or article. S.H.A. has disclosed that he serves on a Association Committee on Research. J Neuropsychiatry Clin Neurosci scientific advisory board for Neuraltus Pharmaceuticals Inc.; has 2009;21:75-87 received a speaker honorarium from Avanir Pharmaceuticals 15. Nuedexta (dextromethorphan hydrobromide and quinidine sulfate) capsules. 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J Pharmacol Exp Ther 1987;242:713-20 18. Musacchio JM, Klein M, Canoll PD. Dextromethorphan and sigma ligands: Acknowledgments common sites but diverse effects. Life Sci 1989;45:1721-32 The authors thank Laura Truskowski of INC Research for statis- 19. Werling LL, Keller A, Frank JG, Nuwayhid SJ. A comparison of the binding tical analysis of the data; INC Research for data collection and profiles of dextromethorphan, memantine, fluoxetine and amitriptyline:

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treatment of involuntary emotional expression disorder. Exp Neurol 2007;207: 29. Rooney J, Byrne S, Heverin M, et al. Survival analysis of Irish amyotrophic 248-57 lateral sclerosis patients diagnosed from 1995–2010. PLoS One 2013;8: 20. Zhang Y, Britto MR, Valderhaug KL, et al. Dextromethorphan: e74733 enhancing its systemic availability by way of low-dose quinidine- 30. Zoccolella S, Beghi E, Palagano G, et al.; SLAP Registry. Analysis of survival mediated inhibition of cytochrome P4502D6. Clin Pharmacol Ther and prognostic factors in amyotrophic lateral sclerosis: a population based 1992;51:647-55 study. J Neurol Neurosurg Psychiatry 2008;79:33-7 21. Pope LE, Khalil MH, Berg JE, et al. Pharmacokinetics of dextromethorphan 31. Murphy M, Quinn S, Young J, et al. Increasing incidence of ALS in Canterbury, after single or multiple dosing in combination with quinidine in extensive and New Zealand: a 22-year study. Neurology 2008;71:1889-95 poor metabolizers. J Clin Pharmacol 2004;44:1132-42 32. del Aquila MA, Longstreth Jr WT, McGuire V, et al. Prognosis in amyotrophic 22. Brooks BR, Thisted RA, Appel SH, et al.; AVP-923 ALS Study Group. lateral sclerosis: a population-based study. Neurology 2003;60:813-19 Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: 33. Chio` A, Mora G, Leone M, et al.; Piemonte and Valle d’Aosta Register for a randomized trial. Neurology 2004;63:1364-70 ALS (PARALS). Early symptom progression rate is related to ALS outcome: a 23. Panitch HS, Thisted RA, Smith RA, et al.; Pseudobulbar Affect in Multiple prospective population-based study. Neurology 2002;59:99-103 Sclerosis Study Group. Randomized, controlled trial of dextromethorphan/ 34. Logroscino G, Traynor BJ, Hardiman O, et al.; EURALS. Descriptive epidemi- quinidine for pseudobulbar affect in multiple sclerosis. Ann Neurol ology of amyotrophic lateral sclerosis: new evidence and unsolved issues. 2006;59:780-7 J Neurol Neurosurg Psychiatry 2008;79:6-11 24. Pioro EP, Brooks BR, Cummings J, et al.; Safety, Tolerability, and Efficacy 35. Millul A, Beghi E, Logroscino G, et al. Survival of patients with amyotrophic Results Trial of AVP-923 in PBA Investigators. Dextromethorphan plus lateral sclerosis in a population-based registry. Neuroepidemiology ultra low-dose quinidine reduces pseudobulbar affect. Ann Neurol 2010; 2005;25:114-19 68:693-702 36. Quinidine Sulfate Tablets USP Revised: June 2005 Rx only. Available at: 25. Gil J, Funalot B, Verschueren A, et al. Causes of death amongst French http://pi.watson.com/data_stream.asp?product_group¼1306&p¼pi [Last patients with amyotrophic lateral sclerosis: a prospective study. Eur J accessed 14 March 2014] Neurol 2008;15:1245-51 37. Holford NH, Coates PE, Guentert TW, et al. The effect of quinidine and its 26. Spataro R, Lo Re M, Piccoli T, et al. Causes and place of death in Italian metabolites on the electrocardiogram and systolic time intervals: concentra- patients with amyotrophic lateral sclerosis. Acta Neurol Scand 2010; tion–effect relationships. Br J Clin Pharmacol 1981;11:187-95 122:217-23 38. Coplen SE, Antman EM, Berlin JA, et al. Efficacy and safety of quinidine 27. Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in therapy for maintenance of sinus rhythm after cardioversion. A meta-analysis amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med of randomized control trials. Circulation 1990;82:1106-16 1994;330:585-91 39. Morganroth J, Goin JE. Quinidine-related mortality in the short-to-medium- 28. Louwerse ES, Weverling GJ, Bossuyt PM, et al. Randomized, double-blind, term treatment of ventricular arrhythmias. A meta-analysis. Circulation controlled trial of acetylcysteine in amyotrophic lateral sclerosis. Arch Neurol 1991;84:1977-83 1995;52:559-64 40. Grace AA, Camm AJ. Quinidine. N Engl J Med 1998;338:35-45 Downloaded by ["University at Buffalo Libraries"] 19:52 28 November 2017

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Dextromethorphan Plus Ultra Low-Dose Quinidine Reduces Pseudobulbar Affect

Erik P. Pioro, MD, PhD,1 Benjamin Rix Brooks, MD,2 Jeffrey Cummings, MD,3 Randolph Schiffer, MD,1 Ronald A. Thisted, PhD,4 Daniel Wynn, MD,5 Adrian Hepner, MD,6 and Randall Kaye, MD6 for the Safety, Tolerability, and Efficacy Results Trial of AVP-923 in PBA Investigators

Objective: To evaluate dextromethorphan combined with ultra low-dose quinidine (DMq) for treating pseudobulbar affect (PBA) in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). Methods: In a 12-week randomized, double-blind trial, ALS and MS patients with clinically significant PBA (a baseline score 13 on the Center for Neurologic Studies–Lability Scale [CNS-LS]) were maintained, twice daily, on placebo, DMq at 30/10mg (DMq-30), or DMq at 20/10mg (DMq-20). Results: In 326 randomized patients (of whom 283, or 86.8%, completed the study), the PBA-episode daily rate was 46.9% (p < 0.0001) lower for DMq-30 than for placebo and 49.0% (p < 0.0001) lower for DMq-20 than for placebo by longitudinal negative binomial regression, the prespecified primary analysis. Mean CNS-LS scores decreased by 8.2 points for DMq-30 and 8.2 for DMq-20, vs 5.7 for placebo (p¼ 0.0002 and p¼ 0.0113, respectively). Other endpoints showing statistically significant DMq benefit included, for both dosage levels, the likelihood of PBA remission during the final 14 days and, for the higher dosage, improvement on measures of social functioning and mental health. Both dosages were safe and well tolerated. Interpretation: DMq markedly reduced PBA frequency and severity, decreasing the condition’s detrimental impact on a patient’s life, with satisfactory safety and high tolerability. The findings expand the clinical evidence that DMq may be an important treatment for patients suffering from the socially debilitating symptoms of PBA. ANN NEUROL 2010;68:693–702

Introduction social functioning and can be highly disabling, owing in 11 seudobulbar affect (PBA) is a neurologic condition part to the stigma attached to loss of emotional control. Pcharacterized by involuntary outbursts of laughing Yet even with such a significant burden of illness, PBA and/or crying incongruous or disproportionate to the appears to be poorly recognized and consequently is 11,12 patient’s emotional state.1 The condition, hypothesized to undertreated. arise from disconnection of brainstem structures from In settings of ALS or MS, dextromethorphan plus cortical inhibition, is associated with underlying central quinidine (DMQ) has been found to be beneficial in reduc- 13,14 nervous system disorders, including stroke,2 traumatic ing PBA. Dextromethorphan (DM) is known to be a brain injury,3 Alzheimer disease,4 amyotrophic lateral scle- low-affinity, noncompetitive antagonist of the N-methyl-d- 15 rosis (ALS),5–7 and multiple sclerosis (MS).8 Prevalence aspartate glutamate receptor, and also a sigma-receptor 16 studies have reported that it affects 11% of patients 1 year agonist. To block its first-pass metabolism, it was originally after a stroke,2 11% of patients during the first year after coadministered with low-dose quinidine (Q), a potent cyto- traumatic brain injury,9 18% of patients with Alzheimer chrome P450 2D6 inhibitor,17 at DMQ dosage of 30/30mg disease,4 10% of patients with MS,8 and 49% of patients in a capsule taken twice daily. Without such blockade, DM with ALS.10 In addition to the effects of the underlying blood levels in some ALS patients have been undetectably disorder, PBA can have a severe impact on well-being and low even following DM dosage as high as 750mg/day.17 In

View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.22093

Received Feb 24, 2010, and in revised form Apr 30, 2010. Accepted for publication May 20, 2010.

Address correspondence to Dr Pioro, Director, Section of ALS and Related Disorders, Department of Neurology, Neurological Institute, Cleveland Clinic, Desk S90, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: [email protected]

From the 1Cleveland Clinic, Cleveland, OH; 2Carolinas Medical Center, Charlotte, NC; 3David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA; 4University of Chicago, Chicago IL; 5Consultants in Neurology, Northbrook, IL; and 6Avanir Pharmaceuticals, Aliso Viejo, CA.

VC 2010 American Neurological Association 693 ANNALS of Neurology atrial fibrillation and flutter, Q is utilized for conversion as well as reduction in frequency of relapse. However, Q doses are often in excess of 1,000 to 1,600mg/day and may affect cardiac function in ways that include prolongation of the QTc interval,18 whichinturnmaybeassociatedwithriskof ventricular arrhythmias.19 In the treatment of PBA, a formal pharmacokinetic/pharmacodynamic analysis has predicted that the Q dosage can be reduced to 10mg per capsule (ultra low dosage, q), as a treatment referred to as DMq, with maintained efficacy and a decreased potential for proarrhythmic risk.20 The present 12-week trial was designed to evaluate DMq at 30/10mg and at 20/10mg twice daily versus placebo for treating PBA in patients with ALS or MS. An FIGURE 1: Subjects’ disposition. DMq-30 5 dextromethorphan additional objective was to determine the pharmacokinetic combined with ultra low-dose quinidine at 30/10mg; DMq-20 5 parameters of each DMq formulation in a subset of the DMq at 20/10mg. study population, as will be reported separately. months or of MS or probable MS (by McDonald criteria23). Patients and Methods Patients were excluded for any evidence of clinically significant abnormality on screening electrocardiogram, a family history of Design congenital QT-interval prolongation syndrome, a resting respi- This was a 12-week, randomized, double-blind, placebo-con- ratory rate outside the range of 12 to 20/min, or a resting diur- trolled, 3-arm, parallel-group study conducted at 60 centers in the nal oxygen saturation <95%. Patients were also excluded for United States and South America between December 2007 and any presence or history of major psychiatric disturbance, includ- March 2009. Patients completed screening procedures 1 to 4 ing current symptoms of a depressive disorder (or a score >19 weeks before their baseline visit. At the screening visit, those meet- on the Beck Depression Inventory–II [BDI-II]24); major sys- ing all inclusion/exclusion criteria (see below) were randomized temic disease or organ dysfunction capable of interfering with (1:1:1) to receive placebo, DM 30mg þ Q 10mg (DMq-30), or study assessments or putting the patient at risk; and exacerba- DM 20mg þ Q 10mg (DMq-20). For the first treatment week, tion of the patient’s underlying ALS or MS within the previous patients took a single capsule of study drug in the morning. Dur- 2 months. Women with childbearing potential were required to ing weeks 2 through 12, they took study drug once in the morn- use a medically acceptable form of birth control; pregnant or ing and once in the evening. Follow-up visits occurred at 2, 4, 8, lactating women were excluded. and 12 weeks. In addition, for 1 week prior to baseline and throughout the trial, patients were required to maintain a diary recording the daily number of laughing and/or crying episodes Efficacy Assessments experienced, the medications they took, and any adverse experien- The primary efficacy outcome was a patient’s change from base- ces. Patients completing the study were eligible to continue treat- line in the number of PBA episodes (laughing and/or crying) ment in a 12-week open-label phase with DMq-30 twice daily. per day, as recorded in the patient’s diary. Diary data also The study protocol was approved by local institutional yielded, as secondary outcomes, a responder analysis (the pro- review boards or independent ethics committees and was con- portion of patients with an improvement from baseline PBA ducted in accordance with Good Clinical Practice Consolidated rate, assessed across all degrees of improvement); number of Guidance, as approved by the International Conference on Har- episode-free days; and occurrence of remission from PBA monization (1997), and also with local or national laws and (defined by absence of episodes during the study’s final 14 regulations. Prior to entry, study procedures and risks were days). Additional secondary outcomes were a patient’s change explained to each subject, and written informed consent was from baseline on CNS-LS, which was administered at baseline obtained. The study’s randomization code (blocked by center and at each follow-up visit, and on BDI-II, the Neuropsychiat- and by underlying neurological disorder) was computer-gener- ric Inventory (NPI),25 and the Medical Outcomes Study 36- ated, and study drug was supplied in blister packs of identical- Item Short-Form Health Survey Version 1.0 (SF-36),26 which looking capsules. The sponsor, all patients, and all investigators were administered at baseline and at 12 weeks. were blind to treatment identification and allocation. The CNS-LS is a 7-item self-assessment of PBA severity, validated for measuring PBA in ALS21 and MS.27 Total scores Patients range from 7 to 35; a score 13 is the instrument’s range for For entry, men or women 18 to 80 years old were required to clinical PBA. The BDI-II is a 21-item self-assessment of symp- have clinically significant PBA, with a score 13 on the Center toms of depression. A total score of 14–19 is considered mild, for Neurologic Study–Lability Scale (CNS-LS),21 and a diagno- 20–28 is moderate, and 29–63 is severe. The NPI is a question- sis either of ALS (by El Escorial criteria22) within the past 30 naire covering 12 neuropsychiatric symptom domains; it

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TABLE 1: Patients’ Baseline Characteristics (ITT Population) Characteristic DMq-30 DMq-20 Placebo

No. 110 107 109 Age, mean yr (SD) 53.1 (11.0) 50.8 (11.1) 50.3 (11.9) Females, No. (%) 64 (58.2) 54 (50.5) 59 (54.1) Ethnic origin, No. (%) White 80 (72.7) 80 (74.8) 83 (76.1) Hispanic 21 (19.1) 21 (19.6) 21 (19.3) Black 6 (5.5) 2 (1.9) 4 (3.7) Other 3 (2.7) 4 (3.7) 1 (0.9) Diagnosis, No. (%) ALS 65 (59.1) 68 (63.6) 64 (58.7) MS 45 (40.9) 39 (36.4) 45 (41.3) Time since ALS diagnosis, mean mon (SD) 22.7 (29.8) 16.3 (22.9) 13.4 (18.0) PBA episodes/day, mean (SD) All 4.7 (9.5) 6.8 (12.9) 4.5 (7.6) Laughing 1.7 (3.4) 4.1 (11.8) 2.5 (7.4) Crying 3.0 (6.7) 2.8 (4.2) 2.0 (2.0) CNS-LS score, mean (SD) 19.8 (4.9) 21.0 (5.0) 19.9 (4.7) BDI-II score, mean (SD) 9.4 (6.1) 10.9 (5.8) 10.5 (5.4) NPI score, mean (SD) Frequency 6.2 (6.3) 7.8 (6.7) 7.0 (6.7) Severity 5.8 (3.9) 7.0 (4.5) 6.3 (4.5) SF-36 score, mean (SD) Mental Summary 44.0 (10.9) 44.6 (11.2) 44.9 (10.6) Physical Summary 40.1 (10.1) 37.0 (10.4) 38.5 (9.8) ITT ¼ intent-to-treat; DMq-30 ¼ dextromethorphan combined with ultra low-dose quinidine at 30/10mg; DMq-20 ¼ DMq at 20/10mg; SD ¼ standard deviation; ALS ¼ amyotrophic lateral sclerosis; MS ¼ multiple sclerosis; PBA ¼ pseudobulbar affect; CNS-LS ¼ Center for Neurologic Study–Lability Scale; BDI-II ¼ Beck Depression Inventory Second Edition; NPI ¼ Neuro- psychiatric Inventory; SF-36 ¼ Medical Outcomes Study 36-Item Short-Form Health Survey.

provides a brief, informant-based assessment of neuropsychiatric uration and nocturnal oxygen saturation were measured (with symptoms and caregiver distress. The SF-36 is a 36-item pulse oximetry) at screening and at 2 weeks. Resting diurnal oxy- health-status assessment, with subdomains for Physical Func- gen saturation was also measured at 12 weeks. Clinical laboratory tioning, Role-Physical, Bodily Pain, General Health, Vitality, testing was performed at screening and at 4 and 12 weeks. Social Functioning, Role-Emotional, and Mental Health. Each of 2 summary scores (Mental Component and Physical Com- ponent) is standardized so that 50 represents the US general Statistical Analyses population norm (for 1998). In the intent-to-treat population, comprising all randomized patients, change from baseline in laughing/crying episode rate was analyzed using longitudinal negative binomial regression,28 Safety/Tolerability Assessments with adjustment for baseline rate, diagnosis, and study site. As At all visits, vital signs were measured, 12-lead electrocardiography a sensitivity analysis, change in episode rate was also assessed by was performed, and reports of adverse events (AEs) were obtained. a nonlongitudinal negative binomial model. In addition, 12- Serious AEs were defined as fatal, life-threatening, significantly week change in episode rate was analyzed using the Wilcoxon disabling, or requiring hospitalization. Resting diurnal oxygen sat- rank sum test. For number of episode-free days, a 2-sample t

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patients (60 with ALS and 30 with MS) per treatment group was planned. This size was expected to be sufficient to detect a 36% reduction in mean episode rate for DMq-30 vs placebo with at least 90% power. The study was not powered to test a difference between DMq-30 and DMq-20.

Results Subjects In all, 332 patients were screened, and among them 326 were randomized, 110 to DMq-30, 107 to DMq-20, and 109 to placebo (Fig 1). The main reasons for screening failure were unwillingness to discontinue disallowed medications, CNS-LS score <13, and BDI-II score >19. In all, 283 patients (86.8% of 326) completed the study, including 101 (91.8% of 110) in the DMq-30 group, 88 (82.2% of 107) in the DMq-20 group, and 94 (86.2% of 109) in the placebo group. Demographically and in baseline PBA characteristics, the treatment groups were well matched (Table 1), except for a higher baseline PBA episode rate in the DMq-20 group than in the other groups, and a longer time since ALS diagnosis in the DMq-30 group. At entry, no patient had clinical depression.

Efficacy Over the course of the study, all 3 groups showed substantial reduction in daily PBA episode rates relative to baseline. However, the reduction in daily PBA episode rate was significantly greater in each of the DMq groups than in the placebo group. By longitudinal negative binomial model (predefined primary efficacy analysis), the FIGURE 2: Twelve-week time course of pseudobulbar affect weekly episode rate and Center for Neurologic Study– Lability Scale (CNS-LS) score (intent-to-treat population). Weekly rates (top chart) are shown as change from baseline at each visit in mean daily rates 3 7. CNS-LS scores (bottom chart) are the means at each visit. DMq-30 5 dextromethorphan combined with ultra low-dose quinidine at 30/10mg; DMq-20 5 DMq at 20/10mg. test was used. Changes on CNS-LS, SF-36, BDI-II, and NPI were analyzed with analysis of covariance, using the method of Frison and Pocock.29 Baseline value, study site, and diagnosis were covariates. Observed cases were used in the sensitivity analyses, with no imputation for missing data. All analyses were 2-sided hypothesis tests at the 0.05 significance level. The safety population comprised all patients who took at least 1 dose of study medication. Their AE rates, for types reported by 5% of patients in any treatment group, were compared among groups, and mean change in resting nocturnal oxygen saturation (from baseline to day 15) was assessed by 2-sample t test. FIGURE 3: Responder analysis by treatment group (intent- to-treat population). Each curve graphs the proportion of patients improved with a given degree of improvement Sample Size Calculation from baseline pseudobulbar affect (PBA) rate at endpoint. Based on PBA episode rates in previous studies of DMq for DMq-30 5 dextromethorphan combined with ultra low-dose PBA in ALS13 and in MS,14 a sample size of approximately 90 quinidine at 30/10mg; DMq-20 5 DMq at 20/10mg.

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TABLE 2: Twelve-Week Mean Change on CNS-LS, NPI, and BDI-II Endpoint DMq-30 DMq-20 Placebo CNS-LS No. 103 96 101 Mean change (p vs placebo) 8.2 (0.0002) 8.2 (0.0113) 5.7 BDI-II No. 103 97 101 Mean change (p vs placebo) 1.6 (0.0368) 1.0 (0.2707) 0.02 NPI (frequency) No. 74 79 66 Mean change (p vs placebo) 1.6 (0.6558) 2.6 (0.0938) 1.3 NPI (severity) No. 46 54 48 Mean change (p vs placebo) 0.7 (0.510) 1.6 (0.207) 1.0 CNS-LS ¼ Center for Neurologic Study-Lability Scale; NPI ¼ Neuropsychiatric Inventory; BDI-II ¼ Beck Depression Inventory Second Edition; DMq-30 ¼ dextromethorphan combined with ultra low-dose quinidine at 30/10mg; DMq-20 ¼ DMq at 20/10mg. treatment effect in each DMq group over that seen in On BDI-II, mean improvement was significantly the placebo group was an incremental reduction in PBA greater for DMq-30 than for placebo (see Table 2). On episode rate of 46.9% (p < 0.0001) for DMq-30 com- NPI, total scores showed no significant change for either pared to placebo and 49.0% (p < 0.0001) for DMq-20 dosage vs placebo (see Table 2). On SF-36, improvement compared to placebo. By nonlongitudinal negative bino- was significant for DMq-30 vs placebo on the Mental mial model with constant dispersion (predefined efficacy Summary score and on its subdomains for social func- sensitivity analysis), the additional improvement over pla- tioning and mental health (Table 3). cebo at both dosage levels was also statistically significant (p < 0.0001 and p¼ 0.0370, respectively). The 12-week mean change in daily episode rate was 4.1 for DMq-30 Safety and Tolerability The proportion of patients reporting at least 1 AE was and 3.9 for DMq-20, vs 3.0 for placebo (p¼ 0.0099 similar in all treatment groups, at 82.7% of DMq-30 and p¼ 0.0048, respectively). Weekly rates (daily rates recipients, 79.4% of DMq-20 recipients, and 82.6% of 7) showed significant decrease at all time points assessed, beginning with day 15 (Fig 2, top). Among secondary outcomes, the 12-week mean reduction from baseline CNS-LS score was significantly greater at both DMq dosage levels than for placebo (Table 2), and for DMq-30, the mean reduction was significant at all time points assessed, beginning with day 15 (see Fig 2, bottom). Among secondary outcomes derived from diary data, the proportion of patients with an improvement from their baseline PBA rate was higher for both DMq-30 and DMq-20 than for placebo, across all degrees of improvement (Fig 3). The proportion of patients’ episode-free days was significantly greater for FIGURE 4: Decrease of pseudobulbar affect, as assessed by freedom from episodes and by remission (intent-to-treat DMq-30 than for placebo at all time points assessed, and population). Freedom from episodes (left) was defined as for DMq-20 vs placebo at all time points except day 15 the percentage of episode-free days since the preceding (Fig 4, left). Lastly, the proportion of patients reporting visit. Remission (right) was defined by absence of episodes throughout the study’s final 14 days. DMq-30 5 dextromethor- remission of PBA was significantly greater at both DMq phan combined with ultra low-dose quinidine at 30/10mg; dosage levels than for placebo (see Fig 4, right). DMq-20 5 DMq at 20/10mg.

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TABLE 3: Twelve-Week Mean Changes on SF-36 (ITT Population) SF-36 Domain, DMq-30 DMq-20 Placebo Mean Change (n 5 110) (n 5 107) (n 5 109) (p vs placebo) Mental Summary 4.5 (0.0193) 1.8 (0.6792) 0.3 Vitality 0.9 (0.2972) 5.3 (0.7510) 4.1 Social Functioning 9.3 (0.0033) 1.4 (0.5544) 3.1 Role Emotional 11.6 (0.3658) 1.8 (0.6838) 2.4 Mental Health 5.5 (0.0028) 3.1 (0.4457) 0.3 Physical Summary 0.8 (0.5877) 1.0 (0.9967) 1.3 Physical Functioning 0.9 (0.2972) 5.3 (0.7510) 4.1 Role Physical 3.5 (0.3063) 4.3 (0.2292) 1.8 Bodily Pain 4.1 (0.0740) 5.8 (0.0678) 1.1 General Health 1.5 (0.8703) 3.0 (0.3583) 1.3 SF-36 ¼ Medical Outcomes Study 36-Item Short-Form Health Survey; ITT ¼ intent-to-treat; DMq-30 ¼ dextromethorphan combined with ultra low-dose quinidine at 30/10mg; DMq-20 ¼ DMq at 20/10mg. placebo recipients. Overall, AE incidence was distributed At day 15, the mean change was 0.2 percentage points evenly throughout the study, except for slightly higher in the DMq-30 group and 0.7 percentage points in rates in the DMq-30 and placebo groups during the ini- the DMq-20 group, vs 0.1 for placebo (p¼ 0.794 and tial treatment week. The proportion of patients reporting serious AEs was also similar across groups, at 7.3% (8 TABLE 4: Adverse Events Reported by 5% of patients) in the DMq-30 group, 8.4% (9 patients) in the Any Group (Safety Population)a DMq-20 group, and 9.2% (10 patients) in the placebo group. Two serious AEs, both in the DMq-20 group, Event Type, DMq-30 DMq-20 Placebo No. (%) (n 5 110) (n 5 107) (n 5 109) were reported as possibly treatment related. In 1 of these patients, the event was reported as respiratory depression Fall 22 (20.0) 14 (13.1) 22 (20.2) and ALS progression. The other patient had worsening Dizziness 20 (18.2) 11 (10.3) 6 (5.5) muscle spasticity. Seven deaths were reported, all in ALS Headache 15 (13.6) 15 (14.0) 17 (15.6) patients: 3 in the DMq-30 group, 3 in the DMq-20 group, and 1 in the placebo group. All deaths were classi- Nausea 14 (12.7) 8 (7.5) 10 (9.2) fied by an independent mortality adjudication committee as Diarrhea 11 (10.0) 14 (13.1) 7 (6.4) having a respiratory cause likely to be the result of progres- Somnolence 11 (10.0) 9 (8.4) 10 (9.2) sion of the underlying neurologic disease. No acute decom- Fatigue 9 (8.2) 11 (10.3) 10 (9.2) pensation of respiratory function after initiation of study drug was observed, and no deaths were ascribed to a cardiac Nasopharyngitis 9 (8.2) 6 (5.6) 8 (7.3) cause. Discontinuations due to AEs were more frequent in Urinary tract 8 (7.3) 4 (3.7) 3 (2.8) the DMq-20 group, at 9.3% (10 patients), than in the infection DMq-30 group, at 5.5% (6 patients), or the placebo group, Constipation 7 (6.4) 7 (6.5) 9 (8.3) at 1.8% (2 patients). Among frequently reported AEs Muscle spasms 7 (6.4) 4 (3.7) 10 (9.2) (Table 4), dizziness, nausea, diarrhea, and urinary tract Muscle weakness 6 (5.5) 5 (4.7) 4 (3.7) infection were more frequent for DMq-30 than for placebo, Dysphagia 5 (4.5) 6 (5.6) 4 (3.7) whereas falls, headache, somnolence, fatigue, and other AEs occurred at rates resembling those for placebo. Pain in extremity 5 (4.5) 2 (1.9) 8 (7.3) Vital signs, physical-examination findings, resting Depression 0 1 (0.9) 6 (5.5) diurnal oxygen saturation, and clinical laboratory values aBy MedDRA preferred term, listed by frequency in the showed no significant changes from their baseline means DMq-30 group. in any treatment group. For resting nocturnal oxygen sat- DMq-30 ¼ dextromethorphan combined with ultra low- dose quinidine at 30/10mg; DMq-20 ¼ DMq at 20/10mg. uration, Table 5 compares baseline and day-15 findings.

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TABLE 5: Summary of Nocturnal Oxygen-Saturation Data (Safety Population) Data DMq-30 DMq-20 Placebo (n 5 108 or 106a), (n 5 102 or 100a), (n 5 108 or 109a), n 5 110 n 5 107 n 5 109 Saturation, mean % (SD) At baseline 94.1 (5.4) 94.9 (2.0) 94.6 (2.2) At day 15 94.4 (2.1) 94.1 (2.5) 94.4 (2.2) Mean change 0.2 (2.0) (0.794) 0.7 (2.0) (0.039) 0.1 (2.1) (p vs placebo) Number of events <88%, mean (SD) At baseline 6.9 (12.6) 6.4 (13.9) 6.4 (12.2) At day 15 5.0 (16.0) 5.0 (16.1) 9.0 (17.7) Total time in minutes <88%, mean (SD) At baseline 11.2 (39.2) 9.9 (39.1) 9.1 (23.1) At day 15 4.1 (19.7) 11.0 (41.7) 11.2 (20.9) aFor saturation and desaturation analyses, respectively. DMq-30 ¼ dextromethorphan combined with ultra low-dose quinidine at 30/10 mg; DMq-20 ¼ DMq at 20/10 mg; SD ¼ standard deviation. p ¼ 0.039, respectively). The differences between groups ized in Table 6. At all time points assessed, no DMq recipi- were not clinically significant. Descriptive analyses of desa- ent had a QTc-interval absolute value >480 milliseconds turation data identified no substantial differences between (with Fridericia correction) or a change from baseline >60 groups (see Table 5). QTc-interval changes are summar- milliseconds.

TABLE 6: Summary of QTc-Interval Data (Safety Population) Data DMq-30 (n 5 110) DMq-20 (n 5 107) Placebo (n 5 109) QTcB/QTcF at baseline, mean ms 418.2/406.6 416.4/404.2 416.1/404.7 QTcB/QTcF at day 84, mean ms 420.6/411.8 413.8/405.1 416.8/405.8 QTcB/QTcF change from baseline, 3.0/4.8 1.9/1.0 1.6/1.0 mean ms Proportion of postbaseline ECGs with absolute QTcB/QTcF >450 ms 6.3%/1.9% 4.9%/1.2% 6.1%/2.4% >480 ms 0.2%/0.0% 0.0%/0.0% 0.9%/0.0% >500 ms 0.0%/0.0% 0.0%/0.0% 0.2%/0.0% Proportion of postbaseline ECGs with change from baseline QTcB/QTcF 30–60 ms 7.0%/7.2% 3.9%/2.9% 6.6%/3.5% >60 ms 0.5%/0.0% 0.2%/0.0% 0.5%/0.5% >90 ms 0.0%/0.0% 0.0%/0.0% 0.0%/0.0% DMq-30 ¼ dextromethorphan combined with ultra low-dose quinidine at 30/10mg; DMq-20 ¼ DMq at 20/10mg; QTcB ¼ QT interval corrected for heart rate (Bazett’s formula); QTcF ¼ QT interval corrected for heart rate (Fridericia’s formula); ECG ¼ electrocardiogram.

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Discussion originally formulated, with DM at 30mg per capsule and In this large, double-blind, placebo-controlled study, Q at 30mg, the 12-week discontinuation rate had been 13 both dosage levels of DMq were significantly superior to much higher, at 28% in ALS patients and 25% in MS 14 placebo for reducing PBA episode frequency among patients. The implication is that the improved tolerability patients with underlying ALS or MS, as assessed by lon- demonstrated in the present study may reflect ultra low gitudinal and nonlongitudinal statistical models and also dosing of Q. Usage of dose escalation (with once-daily by mean change in daily PBA episode rate. At both dos- dosing during week 1) may also have contributed. age levels, DMq also significantly reduced the severity of A body of published evidence suggests that PBA 1 PBA, as represented by CNS-LS score. For reduction in may be ameliorated pharmacologically, but the trials episode rate, a prespecified responder analysis showed, at assessing current agents, all of which are being utilized both dosage levels, a substantial difference from placebo off-label, have limitations. In 1979, dopaminergic treat- across all degrees of improvement, despite a strong pla- ment, specifically L-dopa, was reported to be effective for 30 cebo effect (resembling those seen in previous studies13). ‘‘emotional incontinence,’’ but in a follow-up uncon- The differences between DMq and placebo included, at trolled study of L-dopa or amantadine, only 10 of 25 31 both dosage levels, a significantly higher likelihood of recipients responded. Since then, reports have centered PBA remission on DMq than on placebo, suggesting that on antidepressants, notably tricyclic agents (eg, amitripty- 32 33 for large proportions of patients, the active treatment’s line or nortriptyline ) and selective serotonin reuptake 34 35,36 36 amelioration of PBA may be marked. inhibitors (eg, fluoxetine, citalopram, paroxetine, Numerically, the responses to the higher DMq dos- or sertraline37). Overall, the trials have been hampered age were more robust than those to the lower dosage in by small size (12 to 28 subjects, among those referenced several ways, including an earlier improvement in CNS- above) and by methodological problems, such as their LS score, an earlier time to significant difference vs pla- definitions of PBA improvement. Substantial placebo cebo in number of episode-free days, and a slightly effects, as demonstrated in the present study, make greater 12-week mean change vs placebo in PBA daily uncontrolled findings all the more difficult to interpret. episode rate. At the higher dosage, DMq was also associ- In brief, well-controlled data to support current options ated with significant improvement in mental-health are scarce, and no option is currently approved by the measures, by BDI-II and SF-36. Because none of the US Food and Drug Administration. In addition, antide- subjects in this study was clinically depressed, and pressants are associated with incompletely elucidated AE because PBA can result in substantial reduction of quality profiles (including QT-interval prolongation19). 11 of life, this improvement may have been in well-being. In interpreting the present study’s findings, the trial’s Specific improvements on SF-36 subdomains for social limitations should be taken into account. Because its subjects functioning and mental health are further evidence that were carefully selected, the findings should be generalized to the social and psychological disability associated with a broader spectrum of PBA with caution. The study PBA may have been reduced. However, the possibility required, for instance, a baseline CNS-LS score of at least that DMq may have direct antidepressant properties can- 13. Accordingly, the effects of DMq-30 or DMq-20 on not be excluded, and would require further study. Over- milder forms of PBA are unknown. In addition, the study all, the efficacy reported for DMq containing Q at ultra low dosage—10mg per capsule—resembled the benefits enrolled only patients with underlying ALS or MS. Because reported by measures including CNS-LS scores and PBA the pathophysiologic mechanisms causing PBA are probably episode counts in studies of DMq in its original formula- similar regardless of the underlying CNS pathology, DMq tion, in which the Q content per capsule was 30mg.13,14 will likely be effective in reducing symptoms of PBA arising In the present study, both dosage levels were safe. in various brain disease or injury states, much in the same In particular, cardiovascular safety was satisfactory, with way that antispastic medication reduces spasticity, irrespective mild QTc prolongation and no proarrhythmic events. of the underlying condition. Even so, additional studies of Respiratory findings appeared to be consistent with ALS the effect of DMq on PBA in various neurological disorders progression. However, physicians should always exercise could provide enhanced safety, efficacy, and health outcome caution in managing a patient population that has com- insight. Hence, further clinical studies of PBA are warranted. promised respiratory function. Both dosage levels were Nevertheless, the present study represents the largest also well tolerated, with only 13% of DMq recipients and longest double-blind, randomized, placebo-controlled discontinuing during 12 weeks of double-blind treatment. trial of DMq conducted to date in PBA, and also the The overall discontinuation rate was lower for DMq-30, at first to test DMq in PBA patients at ultra low Q dosage. 8%, than for DMq-20, at 18%. In studies of DMQ as Its findings expand the clinical evidence that with

700 Volume 68, No. 5 Pioro et al: Pseudobulbar Affect satisfactory safety and high tolerability, DMq markedly (Vanderbilt Neurology, Medical Center North); David reduces PBA frequency and severity, decreasing the con- Ginsburg, MD (University of Nevada School of Medi- dition’s detrimental impact on a patient’s life. cine); Jonathan Glass, MD (Emory University); Michael Graves, MD (University of California at Los Angeles Acknowledgment School of Medicine); Laurie Gutmann, MD (West Vir- ginia University School of Medicine); Bianca Weinstock- This study was supported by Avanir Pharmaceuticals. Guttman, MD (Buffalo General Hospital); Ghazala Hayat, MD (Saint Louis University); Daragh Heitzman, Potential Conflicts of Interest MD (Texas Neurology, PA); Catherine Lomen-Hoerth, E.P.P. has received research support and compensation for MD (Amyotrophic Lateral Sclerosis Center at University consulting from Avanir Pharmaceuticals. B.R.B. has of California at San Francisco); Carlayne E. Jackson, MD received compensation for consulting from Avanir Phar- (University of Texas Health Science Center); Edward maceuticals, Bayer Healthcare Pharmaceuticals, Biogen Kasarskis, MD (University of Kentucky); Jason Kellogg, Idec, Genentech, and Teva Neuroscience, and has received MD (South Coast Clinical Trials, Inc.); Jonathan Licht, research support from Avanir Pharmaceuticals, Biogen MD (Coordinated Clinical Research); Ann Little, MD Idec, National Institutes of Neurological Disorders and (University of Michigan Health System); Jau-Shin Lou, Stroke Clinical Research Consortium, Novartis, and Teva MD (Oregon Health Science University); Catherine Neuroscience. J.C. has received compensation for consult- Madison, MD (California Pacific Medical Center); Leo ing from Abbott, Acadia, Accera, ADAMAS, Astellas, McCluskey, MD (University of Pennsylvania Health Sys- Avanir Pharmaceuticals, Bristol-Myers Squibb, CoMentis, tem); April McVey, MD (University of Kansas Medical Eisai, Elan, EnVivo, Forest, GlaxoSmithKline, Janssen, Center, Landon Center on Aging); Hiroshi Mitsumoto, Lilly, Lundbeck, Medivation, Merck, Merz, Myriad, MD (Columbia Presbyterian Center); Tahseen Mozaffar, Neuren, Novartis, Pfizer, Prana, Schering Plough, Sonexa, MD (University of California at Irvine); Steven Nash, Takeda, Toyama, and Wyeth, and owns the copyright of MD (Ohio State University Medical Center); Daniel the Neuropsychiatric Inventory. A.H. and R.K. are Newman, MD (Henry Ford Hospital); Oliver Ni, MD employees of and own stock options in Avanir Pharma- (Dean Foundation); Gary Pattee, MD (Neurology Asso- ceuticals. R.S. has received compensation for consulting ciates, Inc.); Terry Heiman-Patterson, MD (Drexel Uni- from Teva and Avanir Pharmaceuticals and owns 300 versity College of Medicine); Erik Pioro, MD, PhD shares of common stock in Johnson & Johnson Corpora- (Cleveland Clinic Foundation); Yvonne Rollins, MD, tion. R.A.T. is a statistical consultant to Avanir PhD (University of Colorado, Denver)(replacing Dr Bjorn Pharmaceuticals, and has been an expert witness on behalf Oskarsson); Jiong Shi, MD (Barrow Neurological Institute of Eli Lilly, Forest Laboratories, Wyeth, Otsuka, Glaxo- of St. Joseph’s Hospital and Medical Center) (replacing Dr SmithKline, and Hoffmann-LaRoche. D.W. has received Timothy Vollmer); Ericka Simpson, MD (Methodist Hos- compensation for consulting from Teva Neurosciences, Pfizer, pital Research Institute); Mark Sivak, MD (Mount Sinai Serono, Acorda Therapeutics, GlaxoSmithKline, Avanir Medical Center)(replacing Dr Dale Lang); Kumaraswamy Pharmaceuticals, and Eli Lilly, and has received research Sivakumar, MD (Neuromuscular Research Center); Brian support from Biogen Idec, Serono, Pfizer, Teva, UCB Steingo, MD (Neurological Associates); Robert Sufit, MD Pharma, PDL BioPharma, BioMS, Sanofi-Aventis, Opexa (Northwestern University); Rup Tandan, MD (University Therapeutics, Genzyme, GlaxoSmithKline, XenoPort, Avanir of Vermont, College of Medicine); Alberto Vasquez, MD Pharmaceuticals, Eli Lilly, and Shire Laboratories. (Suncoast Neuroscience Associates, Inc.); Ashok Verma, MD (University of Miami); Joseph Weissman, MD (Neu- rology Specialists of Decatur Research Center); Ben Wil- liams, MD (Texas Tech University)(replacing Dr Randolph Appendix Schiffer); James Wymer, MD (Upstate Clinical Research, AVP-923 in PBA Trial Investigators LLC); Daniel Wynn, MD (Consultants in Neurology, Ltd.).

USA. Carmel Armon, MD (Baystate Medical Center); SOUTH AMERICA. Alberto Francisco Rodriguez Richard Bedlack, MD (Duke University); Kevin Boylan, Alfici, MD (Instituto Me´dico Rodriguez Alfici); Dago- MD (Mayo Clinic Jacksonville); Elena Bravver, MD berto Callegaro, MD (Faculdade de Medicina da Uni- (Carolinas Medical Center); Andrea Corse, MD (Johns versidade Sa˜o Paulo); Adriana Josefa Carra´,MD Hopkins University); Merit E. Cudkowicz, MD, MSc (Hospital Britanico Buenos Aires); Edgardo Cristiano, (Massachusetts General Hospital); Dennis Dietrich, MD MD (Hospital Italiano de Buenos Aires); Jefferson (Advanced Neurology Specialists); Peter Donofrio, MD Gomes Fernandes, MD (Hospital Moinhos de Vento);

November, 2010 701 ANNALS of Neurology

Maria Lucia Brito Ferreira, MD (Hospital da Restaura- 15. Choi DW. Dextrorphan and dextromethorphan attenuate glutamate neurotoxicity. Brain Res 1987;403:333–336. çaõ, Secretaria Estadual da Sau´ de); Soniza Vieira Alves 16. Musacchio JM, Klein M, Paturzo JJ. Effects of dextromethorphan site Leon, MD (Hospital Universita´rio Clementino Fraga ligands and allosteric modifiers on the binding of (þ)-[3H]3-(-3- Filho); Geraldine Luetic, MD (Instituto Neurociencias hydroxyphenyl)-N-(1-propyl)piperidine. Mol Pharmacol 1989;35:1–5. Rosario); Antonio Pereira Gomes Neto, MD (Santa 17. Zhang Y, Britto MR, Valderhaug KL, et al. Dextromethorphan: Casa de Misericordia de Belo Horizonte); Martin Alejan- enhancing its systemic availability by way of low-dose quinidine- mediated inhibition of cytochrome P4502D6. Clin Pharmacol Ther dro Nogue´s, MD (FundaciońparalaLuchadelasEnfer- 1992;51:647–655. medades Neurolo´gicas de la Infancia); Miguel Angel 18. Holford NH, Coates PE, Guentert TW, et al. The effect of quini- Pagano, MD (Fundacioń contra las Enfermedades Neuro- dine and its metabolites on the electrocardiogram and systolic time intervals: concentration-effect relationships. Br J Clin Pharma- lo´gicas del Envejecimiento); Gustavo Martin Petracca, col 1981;11:187–195. MD (Instituto de Neurociencias Buenos Aires); Roberto 19. De Ponti F, Poluzzi E, Montanaro N. QT-interval prolongation by Daniel Rey, MD (Instituto Argentino InvestigaciońNeu- non-cardiac drugs: lessons to be learned from recent experience. rolo´gica); Rosana Herminia Scola, MD (Hospital de Eur J Clin Pharmacol 2000;56:1–18. Clıńicas, UFPR); Adriana Nora Tarulla, MD (Policlıńico 20. Brooks BR, Cummings J, Pioro EP, et al. Pharmacokinetic/pharmacodynamic modeling of dextromethorphan/quinidine for a study Bancario); Andres Marıá Villa, MD (Hospital General de in pseudobulbar affect. Presented at: American Neurological Agudos Ramos Mejıá); Carlos Alejandro Vrech, MD Association’s 133rd Annual Meeting; September 21–24, 2008; Salt Lake City, Utah [abstract T 172]. (Hospital Militar Regional de Co´rdoba). 21. Moore SR, Gresham LS, Bromberg MB, et al. A self report measure of affective lability. J Neurol Neurosurg Psychiatry 1997;63:89–93. References 22. Brooks BR, Miller RG, Swash M, et al. El Escorial revisited: revised 1. Dark FL, McGrath JJ, Ron MA. Pathological laughing and crying. criteria for the diagnosis of amyotrophic lateral sclerosis. Amyo- Aust N Z J Psychiatry 1996;30:472–479. troph Lateral Scler Other Motor Neuron Disord 2000;1:293–299.

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702 Volume 68, No. 5 Hammond et al. BMC Neurology (2016) 16:89 DOI 10.1186/s12883-016-0609-0

RESEARCH ARTICLE Open Access PRISM II: an open-label study to assess effectiveness of dextromethorphan/ quinidine for pseudobulbar affect in patients with dementia, stroke or traumatic brain injury Flora M. Hammond1*, David N. Alexander2,AndrewJ.Cutler3,StephenD’Amico4, Rachelle S. Doody5, William Sauve6, Richard D. Zorowitz7, Charles S. Davis8,PaulShin9,FredLedon9, Charles Yonan9,AndreaE.Formella9 and Joao Siffert9

Abstract Background: Phase 3 trials supporting dextromethorphan/quinidine (DM/Q) use as a treatment for pseudobulbar affect (PBA) were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). The PRISM II study provides additional DM/Q experience with PBA secondary to dementia, stroke, or traumatic brain injury (TBI). Methods: Participants in this open-label, multicenter, 90-day trial received DM/Q 20/10 mg twice daily. The primary outcome was the Center for Neurologic Study-Lability Scale (CNS-LS), assessing change in PBA episode frequency and severity. The CNS-LS final visit score was compared to baseline (primary analysis) and to the response in a previously conducted placebo-controlled trial with DM/Q in patients with ALS or MS. Secondary outcomes included change in PBA episode count and Clinical Global Impression of Change with respect to PBA as rated by a clinician (CGI-C) and by the patient or caregiver (PGI-C). Results: The study enrolled 367 participants with PBA secondary to dementia, stroke, or TBI. Mean (standard deviation [SD]) CNS-LS score improved significantly from 20.4 (4.4) at baseline to 12.8 (5.0) at Day 90/Final Visit (change, −7.7 [6.1]; P < .001, 95 % CI: −8.4, −7.0). This magnitude of improvement was consistent with DM/Q improvement in the earlier phase-3, placebo-controlled trial (mean [95 % CI] change from baseline, −8.2 [−9.4, −7.0]) and numerically exceeds the improvement seen with placebo in that study (−5.7 [−6.8, −4.7]). Reduction in PBA episode count was 72.3 % at Day 90/Final Visit compared with baseline (P < .001). Scores on CGI-C and PGI-C showed that 76.6 and 72.4 % of participants, respectively, were “much” or ”very much” improved with respect to PBA. The most frequently occurring adverse events (AEs) were diarrhea (5.4 %), headache (4.1 %), urinary tract infection (2.7 %), and dizziness (2.5 %); 9.8 % had AEs that led to discontinuation. Serious AEs were reported in 6.3 %; however, none were considered treatment related. Conclusions: DM/Qwasshowntobeaneffectiveandwell-tolerated treatment for PBA secondary to dementia, stroke, or TBI. The magnitude of PBA improvement was similar to that reported in patients with PBA secondary to ALS or MS, and the adverse event profile was consistent with the known safety profile of DM/Q. (Continued on next page)

* Correspondence: [email protected] Charles Yonan and Joao Siffert are former employees of Avanir Pharmaceuticals, Inc. 1Physical Medicine and Rehabilitation, Indiana University School of Medicine, Rehabilitation Hospital of Indiana, 4141 Shore Drive, Indianapolis, IN 46254, USA Full list of author information is available at the end of the article

© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hammond et al. BMC Neurology (2016) 16:89 Page 2 of 12

(Continued from previous page) Trial registration: Clinicaltrials.gov, NCT01799941, registered on 25 February 2013 Keywords: Dextromethorphan, Quinidine, Pseudobulbar affect, Dementia, Brain injuries, Stroke, Neuropsychiatric symptoms, Center for neurologic study-lability scale

Background Dextromethorphan hydrobromide and quinidine sul- Affective lability is a commonly described sequela of fate in the fixed combination NUEDEXTA® (DM/Q; multiple neurologic disorders and brain injury. Pseudo- commercially available since 2010 from Avanir Pharma- bulbar affect (PBA) is a type of affect lability character- ceuticals, Inc., Aliso Viejo, CA, USA) is currently the ized by sudden, involuntary, and distressing outbursts of only pharmaceutical agent approved by the US Food and laughing and/or crying that are often exaggerated or dis- Drug Administration for the treatment of PBA [16]. connected from mood state or social context [1–3]. PBA DM, the CNS-active component of the medication, is a episodes tend to be stereotypical, can last from seconds weak, uncompetitive N-methyl-D-aspartate (NMDA) to several minutes, and often occur multiple times per receptor antagonist, a sigma-1 receptor agonist, a sero- day. PBA is thought to occur as a result of injury or dis- tonin and norepinephrine reuptake inhibitor, and an ease that disrupts pathways regulating emotional expres- α3β4 neuronal nicotinic receptor antagonist [17–19]. sion, or affect, including the corticobulbar tracts and However, the mechanism whereby DM exerts its clinical basal ganglia [4, 5]. PBA is diagnosed clinically through a effects is not fully elucidated. Normally, DM is rapidly me- medical and neurologic evaluation and a careful assess- tabolized through the cytochrome P450 2D6 (CYP2D6) ment of symptoms in order to distinguish it from features isoenzyme to dextrorphan, a metabolite that is rapidly glu- of other psychiatric or neurobehavioral conditions such as curonidated, limiting its CNS bioavailability when DM is depression, anxiety disorders, post-traumatic stress dis- administered at approved doses. When administered order, dementia-related agitation and other conditions alone, DM achieves only minimal plasma exposure. Low- that can occur separately or comorbidly with PBA in per- dose quinidine (10 mg) is a potent inhibitor of cytochrome sons with neurologic diseases or brain injuries [2]. P450 2D6 that, when combined with DM, substantially in- PBA episodes can be highly disruptive to everyday life, creases DM bioavailability and enables greater central ner- causing embarrassment, social isolation and, in some vous system exposure. Well-controlled Phase 3 studies cases, impacting the ability to work [6]. Prevalence esti- have shown that the DM/Q combination is efficacious for mates vary by rigor of diagnostic requirements, screen- the treatment of PBA [20–22], and is significantly more ing methodology, and causative neurological disorder; efficacious than DM alone or Q alone [22]. however a registry sample of 5,290 clinic patients with 1 The DM/Q combination was approved in the United of 6 neurologic conditions known to be associated with States for the treatment of PBA, irrespective of the type PBA—Alzheimer’s disease (AD), amyotrophic lateral of neurologic etiology, as a result of phase 3 trials in par- sclerosis (ALS), multiple sclerosis (MS), Parkinson’s dis- ticipants with PBA secondary to ALS or MS [20–22]. ease (PD), stroke, and traumatic brain injury (TBI)— Across the phase 3 trials in patients with MS or ALS, found 36.7 % had a Center for Neurologic Study-Lability DM/Q was generally safe and well tolerated [20–22]. In Scale (CNS-LS) score ≥13, a score that predicted neur- addition, DM/Q was found to be generally well toler- ologist diagnosis of PBA in validation studies for 82 % of ated in a long-term, 52-week safety trial that enrolled patients with ALS and 78 % with MS; 9.3 % of this regis- participants with PBA associated with a wide range of try sample had a CNS-LS ≥21 [5]. Other studies report underlying neurological conditions [23]. To date, there PBA symptom prevalence between 7 and 39 % among have been only limited clinical trial data evaluating participants with dementia [5, 7, 8], 5 to 48 % among the safety and efficacy of DM/Q for PBA in specific those with TBI [7, 9, 10], and 11 to 34 % following stroke and well-defined patient populations beyond MS and [11–13]. However, in everyday practice, PBA symp- ALS. toms are generally under-recognized due to lack of The purpose of the present study (referred to as the routine screening, limited awareness of the condition Pseudobulbar Affect Registry Investigating Symptom and confusion with other neuropsychiatric conditions Management II [PRISM II] trial) was to provide data on [3, 7, 14]. Various drugs have been studied as treat- the effectiveness of DM/Q for the treatment of PBA sec- ments for PBA, including tricyclic antidepressants and ondary to dementia, stroke, and TBI. This article de- selective serotonin reuptake inhibitors, though no scribes the findings for outcomes common to the overall agents in these drug classes have been approved for study population. Outcomes in individual neurologic this use [15]. disease cohorts are reported separately [24–26]. Hammond et al. BMC Neurology (2016) 16:89 Page 3 of 12

Methods baseline; any medication changes, if deemed necessary, Study design were recorded. Potential participants were excluded if The study measured effectiveness by evaluating efficacy, they had severe dementia (Mini-Mental State Examin- safety/tolerability and other patient outcomes when used ation [MMSE] score <10); stroke within 3 months of under usual conditions in patients with dementia, stroke, study enrollment; penetrating TBI; severe depressive dis- or TBI. Adults with PBA secondary to dementia, stroke, order; history or current symptoms of schizophrenia (in- or TBI and a CNS-LS score ≥13 (scale range, 7 [no cluding psychosis), schizoaffective disorder or bipolar symptoms] to 35 [maximum]) were enrolled in an open- disorder; substance/alcohol abuse in the preceding label, 90-day study of DM/Q 20/10 mg twice daily (once 3 years; systemic disease, neurologic condition or brain daily during Week 1). Clinical assessments were per- injury that was unstable or rapidly changing within the formed at baseline, Day 30, and Day 90, with a telephone 3 months prior to enrollment; life expectancy ≤6 months; contact at Day 60. This study was conducted in the contraindication to DM/Q use (including known QT United States at 74 enrolling sites, from 26Feb2013 to interval prolongation); DM/Q use during the previous 30Apr2015, according to Good Clinical Practice and the 6 months; or interventional clinical study participation Declaration of Helsinki. The protocol and study mate- within the preceding 30 days. Written informed consent rials were approved by the institutional review board at was obtained from all participants or from legally autho- each site and registered on www.clinicaltrials.gov. (iden- rized representatives. tifier: NCT01799941). Outcome measures Participants Primary measure Participants were eligible for enrollment if they had a The primary outcome was the change in CNS-LS score clinical diagnosis of PBA based on published criteria and from baseline to Day 90 (or final visit). The CNS-LS was a clinical diagnosis of dementia, stroke, or TBI [2]. PBA completed by the patient or the caregiver acting as a pa- diagnostic criteria were (1) involuntary or exaggerated tient proxy at Day 1 (baseline), Day 30 (visit 1), and Day episodes of emotional expression (i.e., laughing or cry- 90 or early withdrawal (final visit). The CNS-LS is a 7- ing); (2) development of symptoms that represent a item (4 laughing items; 3 crying items), self-report rating change from the person's usual emotional reactivity oc- scale measure of PBA episode frequency and severity curring subsequent to a specified brain disorder; (3) epi- that was validated in persons with ALS and persons with sodes are incongruent with or out of proportion to the MS and is sensitive to change over time and treatment individual's mood state and independent to or in excess effects [20–22]. of a provoking stimulus; and (4) symptoms are not bet- ter accounted for by another disorder, substance abuse, Secondary measures or medication use. Patients were also required to have a Secondary measures included PBA episode count for the CNS-LS score ≥13 [27, 28], the same score required for 7 days preceding each study visit as well as the Clinical entry into phase 3 trials of DM/Q for PBA [20–22]. Global Impression of Change (CGI-C) and Patient (or Eligible participants had documented diagnoses of one Caregiver) Global Impression of Change (PGI-C; 7-point of the following: dementia, (including Alzheimer’s, vas- scales ranging from 1 [very much improved] to 7 [very cular, Lewy body, or frontotemporal dementia; ischemic much worse]) based on overall change in the patient’s or hemorrhagic stroke; or mild, moderate, or severe condition with respect to PBA. In addition, a quality-of- non-penetrating TBI. There were no restrictions on life visual analog scale (QOL-VAS) assessed the degree types of allowed concomitant medications with the ex- to which PBA episodes affected the patient’s overall ception of those contraindicated by the US Prescribing quality of life (11-point scale ranging from 0 [“not at Information [16], specifically monoamine oxidase inhibi- all”]to10[“significantly”]) during the past week and a tors (MAOIs), and drugs that both significantly prolong 5-point Likert-type scale rated patient satisfaction with QT interval and are primarily metabolized by CYP2D6 treatment from 1 [very dissatisfied] to 5 [very satisfied]. (e.g., thioridazine). Other medications typically used by The Folstein Mini-Mental State Examination (MMSE; patients with the studied neurologic conditions (includ- 11-item assessment of orientation, memory, attention, ing those that are metabolized by CYP2D6) were allowed and language scored from 0 to 30) was included as a with the stipulation that medications for management of cognitive assessment [29]. As an additional measure, the dementia, such as memantine or acetylcholinesterase in- Patient Health Questionnaire (PHQ-9; a 9-item assess- hibitors should be stable for at least 6 weeks and other ment of depression symptoms with each item rated 0 neuropsychiatric medications such as anticonvulsants, [not at all] to 3 [nearly every day] based on frequency of antidepressants, antipsychotics, anxiolytics, and sedative/ occurrence over the past 2 weeks, for a total possible hypnotics should be stable for at least 2 months prior to score of 27) was included [30]. Disease-specific Hammond et al. BMC Neurology (2016) 16:89 Page 4 of 12

all assessments except the MMSE for any patients who were unable to do so. The timing of assessments is illus- trated in Fig. 1.

Safety Safety measures included reporting of adverse events (AEs) occurring at any time between study enrollment and up to 30 days after the last dose of DM/Q in the study, as well as vital signs and concomitant medication use.

Statistical analysis The safety analysis set included all participants who received at least 1 dose of DM/Q. The effectiveness analysis set comprised all participants in the safety set who also met all study eligibility criteria, and completed at least 1 post-baseline CNS-LS assessment. The Medical Dictionary for Regulatory Activities (version 15.1) was Fig. 1 Schedule of study assessments. Caregivers completed ratings as used for coding, categorizing, and reporting AEs. proxies for patients who were unable (except for the MMSE). AE = All data were analyzed descriptively. Changes from adverse event; CGI-C = Clinical Global Impression of Change; CNS-LS = Center for Neurologic Study–Lability Scale; MMSE = Mini-Mental State baseline in ratings at Day 30 and 90 were also analyzed Exam; NFI = Neurobehavioral Functioning Inventory; PBA = pseudobulbar inferentially using one-sample t-tests for rating scale affect; PGI-C = patient/caregiver Global Impression of Change; PHQ-9 = 9- measures (CNS-LS, QOL-VAS, MMSE, and PHQ-9) and item Patient Health Questionnaire; QOL-VAS = quality-of-life visual analog a mixed-effects Poisson regression model using number scale; SIS = Stroke Impact Scale of PBA episodes in the past 7 days as the dependent variable to estimate change in PBA episode counts. The functional measures, namely the Neurobehavioral Func- mixed-effects Poisson regression model incorporated tioning Inventory and Stroke Impact Scale were assessed age, gender, and time (Day 30 and Day 90) as fixed ef- in the TBI and stroke cohorts, respectively, and will be fects while allowing for individual differences in baseline reported separately. Caregivers were allowed to complete rate (random-subject effects). The percentage change

Fig. 2 Consort diagram for PRISM II cohort. CNS-LS = center for neurologic study–lability scale Hammond et al. BMC Neurology (2016) 16:89 Page 5 of 12

Table 1 Baseline demographics and clinical characteristics—safety Table 1 Baseline demographics and clinical characteristics—safety analysis set analysis set (Continued) N Characteristic ( = 367) MMSE score, mean (SD)f 23.9 (5.9) Age, mean (SD), y 59.4 (16.5) QOL-VAS, mean (SD) 5.9 (2.6) Age category, n (%) PHQ-9,g mean (SD) 13.5 (5.9) ≥ 65 years 152 (41.4) CNS-LS Center for neurologic study-lability scale, MMSE mini-mental state ≥ 75 years 75 (20.4) examination, PBA pseudobulbar affect, PHQ-9 patient health questionnaire-9, QOL-VAS quality-of-life visual analog scale, SD standard deviation, SSRI selective Gender, n (%) serotonin reuptake inhibitor aOther includes American Indian, Alaskan Native, Native Hawaiian, or other Male 165 (45.0) Pacific Islander b Female 202 (55.0) Psychopharmacologic medications included anticonvulsants, antipsychotics, antidepressants, sedatives/hypnotics or anxiolytics, and benzodiazepine Race, n (%) cIncludes benzodiazepines as sedatives/hypnotics plus clonazepam as an anticonvulsant White/Caucasian 304 (82.8) dTypical antipsychotic use in 1.9 %, and atypical antipsychotic use in 16.6 %; Black/African American 50 (13.6) categories were not mutually exclusive eThe CNS-LS scale ranges from 7 to 35, with higher scores indicating increased Asian 3 (0.8) frequency and severity of PBA episodes f Othera 4 (1.1) Effectiveness analysis set (n = 298) gPHQ-9 scores range from 0 to 27, with higher scores indicating increased Unknown 6 (1.6) severity of depression Ethnicity, n (%) episode count from baseline to a given visit is 1 minus Hispanic/Latino 71 (19.4) the appropriate time parameter (λ). Presence of a caregiver, n (%) 166 (45.2) There was no imputation method for missing data; Place of Residence, n (%) however, if the patient had a Final Visit, that visit was in- Home 303 (82.6) cluded as the Day 90 Visit. If there was no Final Visit, Assisted living 35 (9.5) the Day 30 visit was not carried forward as the subject’s Skilled nursing facility 29 (7.9) Final Visit. The primary analysis tested the null hypothesis that the Primary diagnosis, n (%) mean change in CNS-LS score from baseline to the Day Dementia 134 (36.5) 90/Final Visit was equal to zero; the 95 % confidence Stroke 113 (30.8) interval (CI) was also reported to enable a descriptive TBI 120 (32.7) comparison with the CNS-LS change seen in the pivotal Concomitant medications at baseline phase 3 registration trial (STAR trial) that led to the US (total no. of medications) approval of DM/Q for PBA [20]. Pearson correlation coef- Mean 7.7 ficients were calculated to assess the correlation of CNS- Median (min, max) 7.0 (0, 27) LS scores with other endpoints at baseline, Day 30, and Psychopharmacologic medication use,b n (%) 260 (70.8) Day 90/Final Visit, as well as correlation of change from baseline in CNS-LS with changes in other measures. Any antidepressant 178 (48.5) Tests of significance were 2-tailed and carried out at the SSRIs 103 (28.1) α = .05 level of significance; all analyses were completed Other 83 (22.6) using either SAS v9.2 (SAS Institute Inc., Cary, NC) or Non-selective (tricyclic) 14 (3.8) Stata v12 (StataCorp, College Station, TX). All patients Sedative/hypnotics/anxiolytics 124 (33.8) with data for the given comparison were included. Any benzodiazepinec 109 (29.7) A power calculation was based on mean (SD) CNS-LS change observed from the pivotal phase 3 trial for the Antipsychoticsd 66 (18.0) same dose of DM/Q (20/10 mg twice daily): −8.2 (6.1) Anticonvulsants 92 (25.1) points vs. placebo: −5.7 (5.3) points. Based on these re- CNS-LS scoree,f sults, it was determined that a sample size of 100 pa- Mean (SD) 20.5 (4.4) tients per disease group would provide 80 % power to Median (min, max) 20 (13, 34) detect a CNS-LS mean change of −7.45 points (increase PBA episode count of 1.75 points over assumed true placebo mean change (over 7 days prior to baseline)f of −5.7), or 90 % power to detect a CNS-LS mean − Mean (SD) 21.4 (25.0) change of 7.7 points (increase of 2.0 points over assumed true placebo mean change of −5.7). An interim Median (min, max) 12 (0, 240) analysis, conducted after the first 100 patients Hammond et al. BMC Neurology (2016) 16:89 Page 6 of 12

(regardless of cohort) completed the study, supported at baseline was 20.5 (4.4) and median PBA episode these assumptions of magnitude of the effect and indi- count for the 7 days prior to baseline was 12 (range: cated that a sample size of 100 per disease group would 0, 240). Study participants were receiving a median of provide sufficient (≥80 %) power to meet the protocol- 7[0–27] concomitant medications at baseline; the specified endpoints. In addition to the results for the en- majority (70.8 %) were using least one psychiatric tire study population described here, pre-specified ana- medication, most commonly antidepressants (48.5 %; lyses for the three distinct diagnosis groups (Dementia, Table 1). Nearly three quarters (73.0 %) had concomi- Stroke, and TBI cohorts) were conducted separately and tant cardiovascular disease at baseline, most com- have either been reported in full (Dementia [24]) or have monly hypertension (57.8 %) or hyperlipidemia manuscripts in preparation (Stroke [26] and TBI [25]). (44.4 %), and the majority (88.6 %) had another central nervous system disorder, most commonly depres- Results sion (57.5 %) and anxiety disorder (42.2 %). Patients Of the 394 participants screened, 367 participants with Primary efficacy endpoint PBA (134 with dementia, 113 with stroke, and 120 TBI) Figure 3 depicts the mean (SD) CNS-LS scores at each were enrolled and received at least 1 dose of DM/Q; 271 assessment. Compared with the baseline CNS-LS score, (73.8 %) completed the study through Day 90. Partici- mean (SD) CNS-LS scores at Day 30 (n =297)andDay pant disposition is shown in Fig. 2; early discontinuation 90/Final visit (n = 261) were 15.0 (5.0) and 12.8 (5.0) and from the study occurred most commonly because of represent a statistically significant improvement from AEs (9.3 %) and withdrawal of consent (5.7 %). Sixty- baseline (mean [SD] change at Day 30 of −5.4 [5.5]; 95 % nine patients (18.8 %) were excluded from the effective- CI: −6.1, −4.8; P < .001 and Day 90/Final visit of −7.7 [6.1; ness analysis set because of one or more of the follow- 95 % CI: −8.4, −6.9]; P < .001). Improvement at Day 90/ ing: lack of post-baseline CNS-LS score (n = 41), failure Final Visit was consistent with that reported for the same to meet all study eligibility criteria (n = 23), and/or site dose of DM/Q in the 12-week phase 3 pivotal trial that noncompliance (n = 11). A total of 297 patients were in- enrolled patients with PBA secondary to ALS or MS cluded for the Day 30 efficacy analysis, while 261 had (mean [95 % CI] change from baseline, −8.2 [−9.4, −7.0]) evaluable data at Day 90. The baseline demographic and and represents an improvement over the placebo group clinical characteristics of the enrolled cohort (safety ana- from that study (−5.7 [−6.8, −4.7]). lysis set) are described in Table 1. The mean (SD) patient age was 59.4 (16.5) years; 17 % lived in a skilled Secondary analyses nursing or assisted living facility, and 45 % had a PBA episode counts over the 7 days prior to study visit caregiver. In addition, the mean (SD) CNS-LS score decreased from a median of 12 at baseline to 4 at Day

Fig. 3 Mean (SD) CNS-LS Score at Baseline, Day 30, and Day 90 (Effectiveness Analysis Set). CNS-LS scores range from 7 to 35, with higher scores indicating increased frequency and severity of PBA episodes. P values are based on the one sample t-test and represent comparison with baseline. *P < .001 vs. baseline. †The CNS-LS is a patient-reported quantitative measure of the perceived frequency and severity of PBA episodes; CNS-LS scores were not normalized. CNS-LS = Center for Neurologic Study–Lability Scale; PBA = pseudobulbar affect; SD = standard deviation Hammond et al. BMC Neurology (2016) 16:89 Page 7 of 12

Fig. 4 Distribution of PBA Episodes (occurring in the past 7 days) by Visit. Solid bars illustrate the percentage of patients experiencing the given number of episodes shown within the range provided on the x axis. The solid curved line represents the number of PBA episodes that would be predicted based on each patient’s values for the parameters (age, gender and time [Day 30, Day 90]; fixed effects) and baseline rate (random effects) in the mixed-effects Poisson regression model. Patients or daytime caregivers were asked to identify, count, and recall the total episodes of exaggerated or uncontrollable laughing and/or crying over the previous 7 days (prior to visit) at baseline, Day 30, and Day 90. Estimated percent change from baseline for PBA episode count was evaluated via a mixed-effects Poisson regression model for the effectiveness analysis set. *P < .001 vs. baseline

30 and 2 at Day 90. PBA episode frequency by study visit Global ratings by clinicians and participants/caregivers is shown in Fig. 4, using the mixed-effects Poisson indicated the majority believed that during study treatment model estimates. PBA episodes were reduced overall by there had been substantial overall improvement with re- an estimated 57.5 % at Day 30 and 72.3 % at Day 90 spect to PBA (Fig. 5). At Day 90/Final Visit, 76.6 % of pa- compared with baseline (P < .001 for both). Remission of tients were rated by their clinician as “very much PBA episodes (defined as no reported episodes in the improved” or “much improved” on CGI-C and 72.4 % of week before assessment) was reported by 20.3 % of the participants (or caregiver proxies) rated themselves as sample at Day 30 and 35.4 % at Day 90. “very much improved” or “much improved” with Hammond et al. BMC Neurology (2016) 16:89 Page 8 of 12

Fig. 5 90-Day Clinical and Patient Global Impression of Change (Effectiveness Analysis Set). CGI-C is a 7-point investigator-rated scale that assessed overall treatment response (with respect to PBA) from baseline to Day 90/Final Visit, rated as very much improved, much improved, minimally improved, no change, minimally worse, much worse, or very much worse. PGI-C is a 7-point patient/patient’s caregiver rated scale that assessed overall treatment response (with respect to PBA) from baseline to Day 90/Final Visit, rated as very much improved, much improved, minimally improved, no change, minimally worse, much worse, or very much worse. CGI-C = Clinical Global Impression of Change; PGI-C = Patient/Caregiver Global Impression of Change respect to PBA compared with baseline. In contrast, 2 possibly related to DM/Q. The most frequently reported patients reported being “minimally worse” or “much AEs were diarrhea (5.4 %), headache (4.1 %), urinary tract worse” on PGIC (0.8 %) and 3 were reported to be infection (2.7 %), and dizziness (2.5 %). Most AEs were of “minimally” or “much worse” on CGIC (1.1 %). No mild or moderate intensity; severe AEs occurred in 6.0 % patient was reported as “very much worse” on either of participants. In total, 36 (9.8 %) participants had measure. When asked about satisfaction with the AEs that led to study withdrawal, most commonly for treatment, 47.5 % of participants (or caregivers) indi- diarrhea (8 [2.2 %]), dizziness, affective lability, and cated they were very satisfied, 28.0 % somewhat satis- agitation (3 [0.8 %] each. Twenty-three (6.3 %) partici- fied, 11.5 % neutral, 5.4 % somewhat dissatisfied, and pants experienced a serious AE; no serious AE was con- 7.7 % very dissatisfied. sidered treatment related by the study investigators. Two The mean QOL-VAS rating of PBA episode impact deaths occurred during the study (two males ages 91 and on quality of life, the PHQ-9 depressive symptom 83 years with dementia); both were deemed not related to measure, and the MMSE cognitive measure all im- study drug after careful review by the investigators and proved during the study. QOL-VAS scores improved were reported in the dementia cohort manuscript [24]. from a mean (SD) of 5.9 (2.6) at baseline to 2.7 (2.6) at Day 90/Final Visit (mean [SD] change from base- Discussion line, −3.1 [3.2]; P < .001). PHQ-9 scores improved from Earlier placebo-controlled trials performed with DM/Q mean (SD) 13.5 (5.9) at baseline (moderate depression) to included persons with PBA secondary to MS or ALS. 7.5 (5.5) at Day 90/Final Visit (mild depression), represent- The PRISM II open-label, 90-day trial provides expanded ing a mean [SD] change from baseline of −5.6 [6.2] points (P < .001)); mean (SD) MMSE scores increased from 23.9 Table 2 Correlation of change from baseline to day 90/final visit — (5.9) at baseline to 24.3 (6.0) at Day 90/Final Visit (mean in CNS-LS score with other outcome measures effectiveness analysis Set change from baseline, 0.60 (3.0); P < .01). For the cor- P relation analysis, CNS-LS score reduction from base- Variable Pearson Correlation value line to Day 90 was significantly correlated with Weekly PBA episode rate change 0.21 <.001 improvements in all secondary outcomes (weekly PBA QOL-VAS change 0.40 <.001 episode rate, QOL-VAS, PGI-C, CGI-C, PHQ-9, and PGI-C 0.47 <.001 P treatment satisfaction; all < .001) except change in CGI-C 0.48 <.001 MMSE (Table 2). PHQ-9 change 0.32 <.001 − Safety Patient satisfaction score 0.22 <.001 AEs are summarized in Table 3. Of the 367 participants MMSE change 0.01 .877 who received DM/Q and comprised the safety set, 132 CGI-C clinical global impression of changes, CNS-LS Center for neurologic study—lability scale, MMSE mini-mental state exam, PBA pseudobulbar affect, (36.0 %) reported at least 1 AE, including the 55 PGI-C patient/caregiver global impression of change, PHQ-9 9-item patient (15.0 %) who reported at least 1 AE deemed at least health questionnaire, QOL-VAS quality-of-life visual analog scale Hammond et al. BMC Neurology (2016) 16:89 Page 9 of 12

Table 3 Summary of adverse events—safety analysis set consistent across the three cohorts including patients AE Summary, n (%) (N = 367) with stroke, dementia and TBI. The mean (12.8) CNS- Any AE 132 (36.0) LS score at study endpoint was below the minimum AE intensity threshold required for study inclusion. Since this study allowed caregivers to complete assessments for patients Mild 67 (18.3) who were unable to do so, the planned statistical ana- Moderate 72 (19.6) lyses allowed for an evaluation of caregiver-completed Severe 22 (6.0) vs. patient-completed outcomes. This was done for the Unknown 7 (1.9) dementia cohort, and as previously described, caregivers Treatment-related AEs 55 (15.0) generally reported greater PBA symptom change than Treatment-related AE intensity patients, but between group differences were only statistically significant (P < .001) for the estimated PBA epi- Mild 23 (6.3) sode count reduction (57.7 % for patient-reported vs. Moderate 28 (7.6) 77.2 % for caregiver-reported ratings) [24]. Severe 7 (1.9) Improvement was also observed in all other second- Unknown 3 (0.8) ary endpoints, including a clinical meaningful reduc- Serious AEs 23 (6.3) tion in PHQ-9 scores (minimal clinically important Treatment-related serious AEs 0 difference for the PHQ-9 has been estimated to be a 5 point change [31]; mean change observed in this AEs leading to discontinuation 36 (9.8) trial was −5.6). In addition, DM/Q was well tolerated, Frequency of AEs by preferred term with 9.8 % of participants having AEs leading to dis- (occurring in >1 % of patients) continuation; the most frequent AEs were diarrhea Diarrhea 20 (5.4) (5.4 %), headache (4.1 %), urinary tract infection Headache 15 (4.1) (2.7 %), and dizziness (2.5 %). Urinary tract infection 10 (2.7) Dizziness 9 (2.5) Clinical implications Nausea 6 (1.6) Although the present study was open label, results appear to be clinically meaningful, consistent across study Fall 6 (1.6) cohorts, and consistent with those seen in well- Fatigue 5 (1.4) controlled, phase 3 trials of DM/Q. The clinical rele- Somnolence 5 (1.4) vance of CNS-LS score reductions from baseline to Day Dry mouth 4 (1.1) 90/Final Visit is reflected in corresponding reductions in Gastroesophageal reflux disease 4 (1.1) PBA episodes and improvements on other secondary Agitation 4 (1.1) measures, including clinician and patient global impres- sions with respect to PBA and satisfaction with treat- Peripheral edema 4 (1.1) ment. CNS-LS reduction was moderately but AE adverse event significantly correlated with improvements in all secondary outcomes (weekly PBA episode rate, QOL-VAS, safety and efficacy data for DM/Q in a broader patient PGI-C, CGI-C, PHQ-9, and treatment satisfaction; all P population and is the first prospectively conducted, sys- < .001) with the exception of the MMSE. While the mea- tematic study to evaluate DM/Q effectiveness for PBA sured outcomes are directionally related, the lack of occurring subsequent to dementia, stroke, or TBI. The strong correlation (all Pearson’s coefficients were < .5) inclusion criteria defined within this trial allowed for a suggests that changes in CNS-LS and other outcomes patient population that more closely resembles “real-life” are not solely reflective of changes in PBA episode num- clinical circumstances (e.g., participants in this trial were ber and may reflect other aspects of PBA episodes, such taking a median of 7 concomitant medications, about as episode intensity, subjective perception, functioning half were on antidepressants and nearly 20 % were in an related to these episodes, or other factors not readily ap- assisted living or skilled nursing facility). parent from these data. Substantial improvement in clinical symptoms of PBA A pre-specified analysis for this trial assessed the 95 % were seen at both post-baseline assessments with a −7.7 CI for mean change from baseline in CNS-LS scores in point (SD 6.1) reduction in CNS-LS score and a 72.3 % order to enable descriptive comparisons with the earlier reduction in PBA episode frequency at Day 90/Final placebo-controlled Phase 3 trial in patients with PBA visit, both of which represented statistically significant secondary to ALS or MS [20]. Although drug perform- differences compared with baseline. Improvements were ance cannot be directly compared across different Hammond et al. BMC Neurology (2016) 16:89 Page 10 of 12

clinical trial populations and settings, PBA symptom im- observations by patient, caregiver, or investigator. Lastly, provement with DM/Q in the current open-label trial is the criteria for the effectiveness analysis population that consistent with what was observed with DM/Q in the required patients to meet all exclusion and inclusion cri- pivotal Phase 3 trial published by Pioro et al. [20], with a teria may have introduced bias. magnitude of improvement larger than observed for the The CNS-LS is validated as a predictive screening group randomized to placebo in that study. These find- assessment for PBA episode frequency and severity ings are also consistent with two other earlier Phase 3 based on studies in patients with ALS and MS; [21, randomized, controlled trials examining the effect of 22] however, this scale has not been specifically vali- DM/Q for PBA in patients with MS or ALS (range, 7.4– dated for use in screening in patient populations with 7.7; Fig. 6). CNS-LS reductions were similar across all 3 dementia, stroke, and TBI. Even so, changes in CNS- disease cohorts included in this PRISM II trial (demen- LS in this study were consistent with improvements tia, stroke, and TBI; range, 7.2–8.5; Fig. 6) [24–26]. in several other measures of clinical relevance for Taken together, data from PRISM II expand on prior ob- PBA (e.g. frequency of PBA episodes), and prior epi- servations of the utility of DM/Q for PBA in MS and demiological studies have shown that CNS-LS scores ALS and provide consistent and clinically meaningful increase with perceived PBA episode burden [5]. evidence of DM/Q effectiveness for PBA in patients with 3 additional common, and disparate neurological etiolo- Conclusions gies, namely dementia, TBI and stroke. Study findings showed that DM/Q 20/10 mg adminis- DM/Q was associated with low incidence of overall tered twice daily in non-blinded fashion over 12 weeks AEs (36 %), treatment-related AEs (15 %), and AEs to participants with PBA secondary to dementia, stroke, leading to withdrawal (9.8 %). Commonly encountered or TBI was generally well tolerated and was associated AEs were consistent with the safety data from con- with improvements in CNS-LS scores and reductions in trolled studies with DM/Q and information included PBA episodes. These observations are consistent with in the approved product label; no new safety signals those seen in the well-controlled phase 3 trials of DM/Q emerged in this clinical trial, and none of the re- conducted in those with PBA secondary to ALS or MS. ported serious AEs (6.3 %) were deemed by investiga- Improvement in PBA symptoms was associated with clin- tors to be treatment related. ically meaningful improvements in CGI-C and PGI-C rat- Limitations of this study are primarily related to its ings with respect to PBA. The effectiveness of DM/Q for open-label design without an active or placebo compara- PBA secondary to these conditions is consistent with the tor group. In addition, use of self-reported measures proposed pathophysiology of PBA, which suggests symp- may be susceptible to subjective bias based on toms arise when there is disruption or damage to brain

Fig. 6 Mean CNS-LS Scores Across DM/Q Studies for PBA Secondary to Diverse Neurologic Conditions. *DM/Q 30/30 mg twice daily; †DM/Q 20/10 mg twice daily. ‡Improvement from baseline in mean CNS-LS (SE). 99-AVR-102 (4 week study comparing DM/Q to DM or Q monotherapy): End of study is the mean of the CNS-LS scores for Days 15 and 29; P = 0.001 vs. dextromethorphan comparator and P < 0.001 vs quinidine comparator. 02-AVR-106 (12 week DBPC study): End of study is the mean of the CNS-LS scores on Days 15, 29, 57, and 85; P < 0.0001 vs. placebo. 07-AVR-123 (12 week DBPC study): End of study is at Week 12 intent to treat; P < 0.05 vs. placebo. PRISM II: End of study is at Day 90/Final Visit; P < 0.001 vs. baseline in all 3 cohorts. ALS = amyotrophic lateral sclerosis; CNS-LS = Center for Neurologic Study–Lability Scale; DM/Q = dextromethorphan/quinidine; MS = multiple sclerosis; PBA = pseudobulbar affect; TBI = traumatic brain injury; SE = standard error Hammond et al. BMC Neurology (2016) 16:89 Page 11 of 12

pathways regulating emotional expression, regardless of Avanir Pharmaceuticals, Inc., Axovant, AZ Therapies, Biogen, Cerespir, Forum, the specific underlying neurologic condition. Genentech, Hoffman LaRoche, Shanghai Green Valley, Suven, Transition, vTv, and Takeda; holds stock options in AZ Therapies and QR Pharma, and has funding from the National Institutes of Aging and State of Texas. William Additional files Sauve is a faculty member of the Neuroscience Education Institute, is an advisor to Avanir Pharmaceuticals, Inc., and has served as a speaker for Avanir, Pharmaceuticals, Inc., Otsuka, and Sunovion. Richard Zorowitz, has Additional file 1: Institutional Review Boards. File contains a listing consulted within the past 12 months for: Avanir Pharmaceuticals, Inc. as a location and members of Institutional Review Boards approving the study member of the PRISM II Steering Committee; and has stock ownership in protocol. (PDF 30 kb) health care companies including: Various Mutual Funds. He is a consultant for Allergan, Inc., and served on data safety monitoring boards for research Abbreviations projects sponsored by SPR Therapeutics and NexStim. Charles Davis is a AD, Alzheimer’s disease; AE, adverse event; ALS, amyotrophic lateral sclerosis; consultant to Avanir Pharmaceuticals, Inc. Paul Shin, Fred Ledon, Charles CGI-C, Clinical Global Impression of Change; CI, confidence interval; CNS-LS, Yonan, Andrea Formella and João Siffert are employees of Avanir Center for Neurologic Study–Lability Scale; CYP2D6, cytochrome P450 2D6; DM/ Pharmaceuticals, Inc. Q, dextromethorphan/quinidine; MMSE, Mini-Mental State Examination; MS, multiple sclerosis; NFI, neurobehavioral functioning inventory; NMDA, N-methyl- Consent for publication D-aspartate; PBA, pseudobulbar affect; PD, Parkinson’sdisease;PGI-C,Patient/ Not applicable. Caregiver Global impression of change; PHQ-9, patient health questionnaire-9; PRISM, Pseudobulbar affect registry investigating symptom management; QOL- Ethics approval and consent to participate VAS, quality-of-life visual analog scale; SD, standard deviation; SE, standard error; An ethics committee reviewed and approved the protocol. Written informed SIS, stroke impact scale; SSRI, selective serotonin reuptake inhibitor; TBI, consent was obtained from all participants or from legally authorized traumatic brain injury. representatives. Additional file 1 provides a list of all IRBs.

Acknowledgements Author details We acknowledge Shereen McIntyre, MBA (clinical data management and 1Physical Medicine and Rehabilitation, Indiana University School of Medicine, data analysis); Shelby Woods, Tracy Maines and Yim Ang (project Rehabilitation Hospital of Indiana, 4141 Shore Drive, Indianapolis, IN 46254, USA. management); Jennifer Lee (CRA); Randall Kaye, MD (study concept design); 2University of California, Los Angeles, CA, USA. 3Florida Clinical Research Center, Rachel Halpern, PhD, and Mike Johnson, MS (statistical analysis) for their LLC, Bradenton, FL, USA. 4Cornerstone Medical Group, Franklin, TN, USA. 5Baylor contributions. Medical writing and editing assistance provided by Peloton College of Medicine, Houston, TX, USA. 6TMS NeuroHealth Centers, Richmond, Advantage, LLC (Parsippany, NJ) and Prescott Medical Communications VA, USA. 7MedStar National Rehabilitation Network, Washington, DC, USA. 8CSD Group (Chicago, IL). The authors thank all study investigators, participants, Biostatistics, Inc., Tucson, AZ, USA. 9Avanir Pharmaceuticals, Inc., Aliso Viejo, CA, and care partners who assisted with this trial. USA.

Funding Received: 22 December 2015 Accepted: 23 May 2016 This study and medical writing and editing services were funded by Avanir Pharmaceuticals, Inc. References Availability of data and materials 1. Schiffer R, Pope LE. Review of pseudobulbar affect including a novel and Data that have been used to draw conclusions within this manuscript are potential therapy. J Neuropsychiatry Clin Neurosci. 2005;17:447–54. reported in full. Data also will be included at www.clinicaltrials.gov using 2. Cummings JL, Arciniegas DB, Brooks BR, Herndon RM, Lauterbach EC, Pioro accession number NCT01799941. EP, et al. Defining and diagnosing involuntary emotional expression disorder. CNS Spectr. 2006;11:1–7. Authors’ contributions 3. Wortzel HS, Oster TJ, Anderson CA, Arciniegas DB. Pathological laughing All authors had full access to the study data and had final responsibility for and crying : epidemiology, pathophysiology and treatment. CNS Drugs. the decision to submit for publication. All authors provided direction on 2008;22:531–45. manuscript content and data presentation. Flora Hammond, MD, wrote the 4. Parvizi J, Coburn KL, Shillcutt SD, Coffey CE, Lauterbach EC, Mendez MF. first draft of the manuscript. All authors provided feedback and approved the Neuroanatomy of pathological laughing and crying: a report of the final version. All authors read and approved the final manuscript. American Neuropsychiatric Association Committee on Research. J Neuropsychiatry Clin Neurosci. 2009;21:75–87. Authors’ information 5. Brooks BR, Crumpacker D, Fellus J, Kantor D, Kaye RE. PRISM: a novel Charles Yonan and Joao Siffert are former employees of Avanir research tool to assess the prevalence of pseudobulbar affect symptoms Pharmaceuticals, Inc. across neurological conditions. PLoS One. 2013;8, e72232. 6. Colamonico J, Formella A, Bradley W. Pseudobulbar affect: burden of illness Competing interests in the USA. Adv Ther. 2012;29:775–98. Flora Hammond has consulted within the past 12 months for: Avanir 7. Work SS, Colamonico JA, Bradley WG, Kaye RE. Pseudobulbar affect: an Pharmaceuticals, Inc. as a member of the PRISM II Steering Committee; has under-recognized and under-treated neurological disorder. Adv Ther. stock ownership in health care companies including: Abbvie Inc SHS, Eli Lilly 2011;28:586–601. & Co, GlaxoSmithKline PLC ADR, Exchange Traded Funds, and Mutual Funds; 8. Starkstein SE, Migliorelli R, Teson A, Petracca G, Chemerinsky E, Manes F, and her academic institution receives funding from the National Institute on et al. Prevalence and clinical correlates of pathological affective display in Disability Independent Living and Rehabilitation Research. David Alexander Alzheimer's disease. J Neurol Neurosurg Psychiatry. 1995;59:55–60. has consulted within the past 12 months for: Avanir Pharmaceuticals, Inc. as 9. Tateno A, Jorge RE, Robinson RG. Pathological laughing and crying a member of the PRISM II Steering Committee. Andrew Cutler has served as following traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2004;16: a consultant for, received research grants from, and served as a speaker for 426–34. Abbott, AstraZeneca, Avanir Pharmaceuticals, Inc., Bristol-Myers Squibb, 10. Zeilig G, Drubach DA, Katz-Zeilig M, Karatinos J. Pathological laughter Forest, GlaxoSmithKline, Lilly, Merck, Novartis, Ortho-McNeil-Janssen, Otsuka, and crying in patients with closed traumatic brain injury. Brain Inj. Pamlab, Pfizer, Shire, Sunovion, Takeda, and Vanda. Stephen D’Amico has 1996;10:591–7. received honoraria as a consultant and speaker for Avanir Pharmaceuticals, 11. House A, Dennis M, Molyneux A, Warlow C, Hawton K. Emotionalism after Inc. He has been a consultant and received research grants from Sanofi, stroke. BMJ. 1989;298:991–4. Merck, AstraZeneca, Bristol-Myers, Novartis, and Takeda Pharmaceuticals. 12. Morris PL, Robinson RG, Raphael B. Emotional lability after stroke. Aust N Z J Rachelle Doody has consulted within the past 12 months for AC Immune, Psychiatry. 1993;27:601–5. Hammond et al. BMC Neurology (2016) 16:89 Page 12 of 12

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Submit your manuscript at www.biomedcentral.com/submit Hammond et al. BMC Neurology (2016) 16:160 DOI 10.1186/s12883-016-0679-z

ERRATUM Open Access Erratum to: PRISM II: an open-label study to assess effectiveness of dextromethorphan/ quinidine for pseudobulbar affect in patients with dementia, stroke or traumatic brain injury Flora M. Hammond1*, David N. Alexander2, Andrew J. Cutler3, Stephen D’Amico4, Rachelle S. Doody5, William Sauve6, Richard D. Zorowitz7, Charles S. Davis8, Paul Shin9, Fred Ledon9, Charles Yonan9, Andrea E. Formella9 and Joao Siffert9

Erratum Reference 1. Hammond FM, Alexander DN, Cutler AJ, D’Amico S, Doody RS, Sauve W, After publication of the original article [1], the authors et al. PRISM II: an open-label study to assess effectiveness of noticed that there were errors in the caption of Fig. 3, dextromethorphan/quinidine for pseudobulbar affect in patients with and the y-axis of Fig. 6 itself. dementia, stroke or traumatic brain injury. BMC Neurol. 2016;16:89. doi:10.1186/s12883-016-0609-0. The following statement should not have been included in the caption of Fig. 3: “CNS-LS scores were not normalized.” The CNS-LS is a rank-order scale, and is not normalized. This statement was included errone- ously and the authors intended on removing it prior to resubmission, but this was unfortunately overlooked. Similarly, the y-axis within Fig. 6 was mislabelled. The CNS-LS scale ranges from 7 to 35, so the y-axis for Fig. 6 should start at a base score of 7 and not zero. The cor- rect and updated version of Fig. 6, in which the data presented remain accurate and are unchanged, is published in this erratum.

Author details 1Physical Medicine and Rehabilitation, Indiana University School of Medicine, Rehabilitation Hospital of Indiana, 4141 Shore Drive, Indianapolis, IN 46254, USA. 2University of California, Los Angeles, CA, USA. 3Florida Clinical Research Center, LLC, Bradenton, FL, USA. 4Cornerstone Medical Group, Franklin, TN, USA. 5Baylor College of Medicine, Houston, TX, USA. 6TMS NeuroHealth Centers, Richmond, VA, USA. 7MedStar National Rehabilitation Network, Washington, DC, USA. 8CSD Biostatistics, Inc., Tucson, AZ, USA. 9Avanir Pharmaceuticals, Inc., Aliso Viejo, CA, USA.

* Correspondence: [email protected] 1Physical Medicine and Rehabilitation, Indiana University School of Medicine, Rehabilitation Hospital of Indiana, 4141 Shore Drive, Indianapolis, IN 46254, USA